75 results on '"Dhelio Batista Pereira"'
Search Results
2. Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations – a study protocol from the clinical and applied research in Chikungunya (REPLICK network)
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Giselle da Silva Duarte, Alexandra D. Jones, Luciano Pamplona de Goes Cavalcanti, Moacyr Jesus Barreto de Melo Rêgo, Guilherme S. Ribeiro, Rosemary J. Boyton, Dhelio Batista Pereira, Julio Henrique Rosa Croda, Fabio Trindade Maranhão Costa, Angela Pinto Duarte, Marcia Edilaine Lopes Consolaro, Rodrigo Guerino Stabeli, Fábio Juliano Negrão, Jose Luiz Proenca-Modena, Juan Miguel Villalobos-Salcedo, Geraldo da Rocha Castelar Pinheiro, Amanda Pinheiro de Barros Albuquerque, Francisca Kalline de Almeida Barreto, Jose Moreira, Idalina Cristina Ferrari, Patricia Martinez Évora, Vânia Ramos Sela da Silva, Marcus Vinicius Guimarães Lacerda, Daniel M. Altmann, REPLICK network, and André M. Siqueira
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Chikungunya ,Cohort ,Brazil ,Rheumatic manifestations ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Chikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course. Methods The study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science – comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site. Discussion Standardized and harmonized patient cohorts are needed to provide better estimates of chronic arthralgia development, the clinical spectra of acute and chronic disease and investigation of associated risk factors. This study is the largest evaluation of the long-term sequelae of individuals infected with CHIKV in the Brazilian population focusing on musculoskeletal manifestations, mental health, quality of life, and chronic pain. This information will both define disease burden and costs associated with CHIKV infection, and better inform therapeutic guidelines.
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- 2023
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3. Population-based genomic study of Plasmodium vivax malaria in seven Brazilian states and across South AmericaResearch in context
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Amy Ibrahim, Emilia Manko, Jamille G. Dombrowski, Mónica Campos, Ernest Diez Benavente, Debbie Nolder, Colin J. Sutherland, Francois Nosten, Diana Fernandez, Gabriel Vélez-Tobón, Alberto Tobón Castaño, Anna Caroline C. Aguiar, Dhelio Batista Pereira, Simone da Silva Santos, Martha Suarez-Mutis, Silvia Maria Di Santi, Andrea Regina de Souza Baptista, Ricardo Luiz Dantas Machado, Claudio R.F. Marinho, Taane G. Clark, and Susana Campino
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Malaria ,Plasmodium ,Plasmodium vivax ,Non-falciparum malaria ,Brazil ,South America ,Public aspects of medicine ,RA1-1270 - Abstract
Summary: Background: Brazil is a unique and understudied setting for malaria, with complex foci of transmission associated with human and environmental conditions. An understanding of the population genomic diversity of P. vivax parasites across Brazil can support malaria control strategies. Methods: Through whole genome sequencing of P. vivax isolates across 7 Brazilian states, we use population genomic approaches to compare genetic diversity within country (n = 123), continent (6 countries, n = 315) and globally (26 countries, n = 885). Findings: We confirm that South American isolates are distinct, have more ancestral populations than the other global regions, with differentiating mutations in genes under selective pressure linked to antimalarial drugs (pvmdr1, pvdhfr-ts) and mosquito vectors (pvcrmp3, pvP45/48, pvP47). We demonstrate Brazil as a distinct parasite population, with signals of selection including ABC transporter (PvABCI3) and PHIST exported proteins. Interpretation: Brazil has a complex population structure, with evidence of P. simium infections and Amazonian parasites separating into multiple clusters. Overall, our work provides the first Brazil-wide analysis of P. vivax population structure and identifies important mutations, which can inform future research and control measures. Funding: AI is funded by an MRC LiD PhD studentship. TGC is funded by the Medical Research Council (Grant no. MR/M01360X/1, MR/N010469/1, MR/R025576/1, MR/R020973/1 and MR/X005895/1). SC is funded by Medical Research Council UK grants (MR/M01360X/1, MR/R025576/1, MR/R020973/1 and MR/X005895/1) and Bloomsbury SET (ref. CCF17-7779). FN is funded by The Shloklo Malaria Research Unit - part of the Mahidol Oxford Research Unit, supported by the Wellcome Trust (Grant no. 220211). ARSB is funded by São Paulo Research Foundation - FAPESP (Grant no. 2002/09546–1). RLDM is funded by Brazilian National Council for Scientific and Technological Development - CNPq (Grant no. 302353/2003–8 and 471605/2011–5); CRFM is funded by FAPESP (Grant no. 2020/06747–4) and CNPq (Grant no. 302917/2019–5 and 408636/2018–1); JGD is funded by FAPESP fellowships (2016/13465–0 and 2019/12068–5) and CNPq (Grant no. 409216/2018–6).
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- 2023
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4. Distinctive genetic structure and selection patterns in Plasmodium vivax from South Asia and East Africa
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Ernest Diez Benavente, Emilia Manko, Jody Phelan, Monica Campos, Debbie Nolder, Diana Fernandez, Gabriel Velez-Tobon, Alberto Tobón Castaño, Jamille G. Dombrowski, Claudio R. F. Marinho, Anna Caroline C. Aguiar, Dhelio Batista Pereira, Kanlaya Sriprawat, Francois Nosten, Robert Moon, Colin J. Sutherland, Susana Campino, and Taane G. Clark
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Science - Abstract
The genetic diversity of Plasmodium vivax strains in South Asia isn’t well described. Here, the authors sequence P. vivax from returning UK travelers and establish South Asian isolates as subpopulation distinct from East African and South East Asian isolates.
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- 2021
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5. An open dataset of Plasmodium vivax genome variation in 1,895 worldwide samples [version 1; peer review: 2 approved]
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Sonia Goncalves, Lemu Golassa, Wasif Khan, Sisay Alemu, Mohammad Shafiul Alam, Pharath Lim, Elizabeth Ashley, Nicholas M Anstey, Bridget E Barber, Jutta Marfurt, Ashenafi Assefa, Dhelio Batista Pereira, Alyssa Barry, Nguyen Hoang Chau, Jun Cao, Fe Espino, Cindy Chu, Ivo Mueller, María Fernanda Villegas, Rick Fairhurst, Thuy-Nhien Nguyen, Yaghoob Hamedi, Matthew J Grigg, Rintis Noviyanti, Ye Htut, Tran Tinh Hien, Nadira Karunaweera, Kimberly J Johnson, Dominic P Kwiatkowski, Srivicha Krudsood, Francois Nosten, Benedikt Ley, Marcus Lacerda, Alejandro Llanos-Cuentas, Yaobao Liu, Tatiana Lopera-Mesa, Milijaona Randrianarivelojosia, Chanthap Lon, Sasithon Pukrittayakamee, Rezika Mohammed, Pascal Michon, Paul N Newton, Chayadol Namaik-larp, Richard D Pearson, Julian C Rayner, Zuleima Pava, Aung P Phyo, Beyene Petros, Awab Ghulam Rahim, Ric N Price, Sasha V Siegel, Angela Rumaseb, Kamala Thriemer, Victoria J Simpson, Marcelo Urbano Ferreira, Alberto Tobon-Castano, Sonam Wangchuk, Ivan D Vélez, Nicholas J White, Thomas E Wellems, Maria F Yasnot, Arjen M. Dondorp, Timothy William, Daniel Yilma, Sarah Auburn, Hidayat Trimarsanto, Abraham Aseffa, Qi Gao, Roberto Amato, Voahangy Andrianaranjaka, Ishag Adam, Kesinee Chotivanich, Olivo Miotto, Chanaki Amaratunga, Eleanor Drury, Diego F. Echeverry, Berhanu Erko, and Abdul Faiz
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malaria ,plasmodium vivax ,genomics ,data resource ,genomic epidemiology ,eng ,Medicine ,Science - Abstract
This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 samples of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new samples contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published samples from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each sample has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr, dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.
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- 2022
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6. Asymptomatic Plasmodium vivax malaria in the Brazilian Amazon: Submicroscopic parasitemic blood infects Nyssorhynchus darlingi
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Gregório Guilherme Almeida, Pedro Augusto Carvalho Costa, Maísa da Silva Araujo, Gabriela Ribeiro Gomes, Alex Fiorini Carvalho, Maria Marta Figueiredo, Dhelio Batista Pereira, Mauro Shugiro Tada, Jansen Fernandes Medeiros, Irene da Silva Soares, Luzia Helena Carvalho, Flora Satiko Kano, Marcia Caldas de Castro, Joseph Michael Vinetz, Douglas Taylor Golenbock, Lis Ribeiro do Valle Antonelli, and Ricardo Tostes Gazzinelli
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Individuals with asymptomatic infection due to Plasmodium vivax are posited to be important reservoirs of malaria transmission in endemic regions. Here we studied a cohort of P. vivax malaria patients in a suburban area in the Brazilian Amazon. Overall 1,120 individuals were screened for P. vivax infection and 108 (9.6%) had parasitemia detected by qPCR but not by microscopy. Asymptomatic individuals had higher levels of antibodies against P. vivax and similar hematological and biochemical parameters compared to uninfected controls. Blood from asymptomatic individuals with very low parasitemia transmitted P. vivax to the main local vector, Nyssorhynchus darlingi. Lower mosquito infectivity rates were observed when blood from asymptomatic individuals was used in the membrane feeding assay. While blood from symptomatic patients infected 43.4% (199/458) of the mosquitoes, blood from asymptomatic infected 2.5% (43/1,719). However, several asymptomatic individuals maintained parasitemia for several weeks indicating their potential role as an infectious reservoir. These results suggest that asymptomatic individuals are an important source of malaria parasites and Science and Technology for Vaccines granted by Conselho Nacional de may contribute to the transmission of P. vivax in low-endemicity areas of malaria. Author summary Malaria still poses as one of the most important parasitic diseases in the world. The advance of molecular diagnosis brought to light the existence of asymptomatic infections, which may represent most of the infections in some areas. Importantly, the role of asymptomatic carriers in the natural history of malaria is not completely understood. Herein we describe the general characteristics of asymptomatic individuals infected with Plasmodium vivax, and provide evidence of their potential as parasitic reservoirs, even when molecular methods fail to detect the infection. Our findings reinforce the need for better diagnostic tests and open a new window of complexity to be considered in control programs.
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- 2021
7. Ribosomal and non-ribosomal PCR targets for the detection of low-density and mixed malaria infections
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Lara Cotta Amaral, Daniela Rocha Robortella, Luiz Felipe Ferreira Guimarães, Jean Ezequiel Limongi, Cor Jesus Fernandes Fontes, Dhelio Batista Pereira, Cristiana Ferreira Alves de Brito, Flora Satiko Kano, Taís Nóbrega de Sousa, and Luzia Helena Carvalho
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Malaria ,Molecular diagnosis ,PCR ,Submicroscopic ,Mixed-malaria infections ,Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background The unexpected high proportion of submicroscopic malaria infections in areas with low transmission intensity challenges the control and elimination of malaria in the Americas. The current PCR-based assays present limitations as most protocols still rely on amplification of few-copies target gene. Here, the hypothesis was that amplification of different plasmodial targets—ribosomal (18S rRNA) and non-ribosomal multi-copy sequences (Pvr47 for Plasmodium vivax and Pfr364 for Plasmodium falciparum)—could increase the chances of detecting submicroscopic malaria infection. Methods A non-ribosomal real-time PCR assay targeting Pvr47/Pfr364 (NR-qPCR) was established and compared with three additional PCR protocols, two of them based on 18S rRNA gene amplification (Nested-PCR and R-qPCR) and one based on Pvr47/Pfr364 targets (NR-cPCR). The limit of detection of each PCR protocol, at single and artificial mixed P. vivax/P. falciparum infections, was determined by end-point titration curves. Field samples from clinical (n = 110) and subclinical (n = 324) malaria infections were used to evaluate the impact of using multiple molecular targets to detect malaria infections. Results The results demonstrated that an association of ribosomal and non-ribosomal targets did not increase sensitivity to detect submicroscopic malaria infections. Despite of that, artificial mixed-malaria infections demonstrated that the NR-qPCR was the most sensitive protocol to detect low-levels of P. vivax/P. falciparum co-infections. Field studies confirmed that submicroscopic malaria represented a large proportion (up to 77%) of infections among asymptomatic Amazonian residents, with a high proportion of infections (~ 20%) identified only by the NR-qPCR. Conclusions This study presents a new species-specific non-ribosomal PCR assay with potential to identify low-density P. vivax and P. falciparum infections. As the majority of subclinical infections was caused by P. vivax, the commonest form of malaria in the Amazon area, future studies should investigate the potential of Pvr47/Pfr364 to detect mixed-malaria infections in the field.
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- 2019
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8. Naturally Acquired Antibody Response to Malaria Transmission Blocking Vaccine Candidate Pvs230 Domain 1
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Bergeline C. Nguemwo Tentokam, Chanaki Amaratunga, Nada A. H. Alani, Nicholas J. MacDonald, David L. Narum, Nichole D. Salinas, Jennifer L. Kwan, Seila Suon, Sokunthea Sreng, Dhelio Batista Pereira, Niraj H. Tolia, Ricardo T. Fujiwara, Lilian L. Bueno, Patrick E. Duffy, and Camila H. Coelho
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malaria ,Plasmodium vivax ,Pvs230 ,transmission-blocking vaccine ,seroreactivity ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Plasmodium vivax malaria incidence has increased in Latin America and Asia and is responsible for nearly 74.1% of malaria cases in Latin America. Immune responses to P. vivax are less well characterized than those to P. falciparum, partly because P. vivax is more difficult to cultivate in the laboratory. While antibodies are known to play an important role in P. vivax disease control, few studies have evaluated responses to P. vivax sexual stage antigens. We collected sera or plasma samples from P. vivax-infected subjects from Brazil (n = 70) and Cambodia (n = 79) to assess antibody responses to domain 1 of the gametocyte/gamete stage protein Pvs230 (Pvs230D1M). We found that 27.1% (19/70) and 26.6% (21/79) of subjects from Brazil and Cambodia, respectively, presented with detectable antibody responses to Pvs230D1M antigen. The most frequent subclasses elicited in response to Pvs230D1M were IgG1 and IgG3. Although age did not correlate significantly with Pvs230D1M antibody levels overall, we observed significant differences between age strata. Hemoglobin concentration inversely correlated with Pvs230D1M antibody levels in Brazil, but not in Cambodia. Additionally, we analyzed the antibody response against Pfs230D1M, the P. falciparum ortholog of Pvs230D1M. We detected antibodies to Pfs230D1M in 7.2 and 16.5% of Brazilian and Cambodian P. vivax-infected subjects. Depletion of Pvs230D1M IgG did not impair the response to Pfs230D1M, suggesting pre-exposure to P. falciparum, or co-infection. We also analyzed IgG responses to sporozoite protein PvCSP (11.4 and 41.8% in Brazil and Cambodia, respectively) and to merozoite protein PvDBP-RII (67.1 and 48.1% in Brazil and Cambodia, respectively), whose titers also inversely correlated with hemoglobin concentration only in Brazil. These data establish patterns of seroreactivity to sexual stage Pvs230D1M and show similar antibody responses among P. vivax-infected subjects from regions of differing transmission intensity in Brazil and Cambodia.
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- 2019
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9. Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria
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Bruno Coelho Rocha, Pedro Elias Marques, Fabiana Maria de Souza Leoratti, Caroline Junqueira, Dhelio Batista Pereira, Lis Ribeiro do Valle Antonelli, Gustavo Batista Menezes, Douglas Taylor Golenbock, and Ricardo Tostes Gazzinelli
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Biology (General) ,QH301-705.5 - Abstract
Neutrophils are the most abundant leukocyte population in the bloodstream, the primary compartment of Plasmodium sp. infection. However, the role of these polymorphonuclear cells in mediating either the resistance or the pathogenesis of malaria is poorly understood. We report that circulating neutrophils from malaria patients are highly activated, as indicated by a strong type I interferon transcriptional signature, increased expression of surface activation markers, enhanced release of reactive oxygen species and myeloperoxidase, and a high frequency of low-density granulocytes. The activation of neutrophils was associated with increased levels of serum alanine and aspartate aminotransferases, indicating liver damage. In a rodent malaria model, we observed intense recruitment of neutrophils to liver sinusoids. Neutrophil migration and IL-1β and chemokine expression as well as liver damage were all dependent on type I interferon signaling. The data suggest that type I interferon signaling has a central role in neutrophil activation and malaria pathogenesis.
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- 2015
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10. Phylogenetic Characterization of Arboviruses in Patients Suffering from Acute Fever in Rondônia, Brazil
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Jackson Alves da Silva Queiroz, Luan Felipo Botelho-Souza, Felipe Souza Nogueira-Lima, Rita de Cássia Pontello Rampazzo, Marco Aurélio Krieger, Miriam Ribas Zambenedetti, Fabricio Klerinton Marchini, Ivo Alberto Borghetti, Dhelio Batista Pereira, Juan Miguel Vilalobos Salcedo, Deusilene Souza Vieira, and Alcione de Oliveira dos Santos
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arboviruses ,phylogenetic ,genotyping ,Microbiology ,QR1-502 - Abstract
The purpose of the study was to classify, through phylogenetic analyses, the main arboviruses that have been isolated in the metropolitan region of Porto Velho, Rondônia, Brazil. Serum samples from patients with symptoms suggesting arboviruses were collected and tested by One Step RT-qPCR for Zika, Dengue (serotypes 1–4), Chikungunya, Mayaro and Oropouche viruses. Positive samples were amplified by conventional PCR and sequenced utilizing the Sanger method. The obtained sequences were aligned, and an evolutionary analysis was carried out using Bayesian inference. A total of 308 samples were tested. Of this total, 20 had a detectable viral load for Dengue, being detected DENV1 (18/20), co-infection DENV1 and DENV2 (1/20) and DENV4 (1/20). For Dengue serotype 3 and for the CHIKV, ZIKV, MAYV and OROV viruses, no individuals with a detectable viral load were found. A total of 9 of these samples were magnified by conventional PCR for sequencing. Of these, 6 were successfully sequenced and, according to the evolutionary profile, 5 corresponded to serotype DENV-1 genotype V, and 1 to serotype DENV-4 genotype II. In the study, we demonstrate co-circulation of the DENV-1 genotype V and the DENV-4 genotype II. Co-circulation of several DENV serotypes in the same city poses a risk to the population and is correlated with the increase of the most severe forms of the disease. Similarly, co-circulation of genetically distinct DENV and the occurrence of simultaneous infections can affect recombination events and lead to the emergence of more virulent isolates.
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- 2020
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11. T follicular helper cells regulate the activation of B lymphocytes and antibody production during Plasmodium vivax infection.
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Maria Marta Figueiredo, Pedro Augusto Carvalho Costa, Suelen Queiroz Diniz, Priscilla Miranda Henriques, Flora Satiko Kano, Mauro Sugiro Tada, Dhelio Batista Pereira, Irene Silva Soares, Olindo Assis Martins-Filho, Dragana Jankovic, Ricardo Tostes Gazzinelli, and Lis Ribeiro do Valle Antonelli
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Although the importance of humoral immunity to malaria has been established, factors that control antibody production are poorly understood. Follicular helper T cells (Tfh cells) are pivotal for generating high-affinity, long-lived antibody responses. While it has been proposed that expansion of antigen-specific Tfh cells, interleukin (IL) 21 production and robust germinal center formation are associated with protection against malaria in mice, whether Tfh cells are found during Plasmodium vivax (P. vivax) infection and if they play a role during disease remains unknown. Our goal was to define the role of Tfh cells during P. vivax malaria. We demonstrate that P. vivax infection triggers IL-21 production and an increase in Tfh cells (PD-1+ICOS+CXCR5+CD45RO+CD4+CD3+). As expected, FACS-sorted Tfh cells, the primary source of IL-21, induced immunoglobulin production by purified naïve B cells. Furthermore, we found that P. vivax infection alters the B cell compartment and these alterations were dependent on the number of previous infections. First exposure leads to increased proportions of activated and atypical memory B cells and decreased frequencies of classical memory B cells, whereas patients that experienced multiple episodes displayed lower proportions of atypical B cells and higher frequencies of classical memory B cells. Despite the limited sample size, but consistent with the latter finding, the data suggest that patients who had more than five infections harbored more Tfh cells and produce more specific antibodies. P. vivax infection triggers IL-21 production by Tfh that impact B cell responses in humans.
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- 2017
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12. Neutrophil paralysis in Plasmodium vivax malaria.
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Fabiana Maria de Souza Leoratti, Silvia Cellone Trevelin, Fernando Queiroz Cunha, Bruno Coelho Rocha, Pedro Augusto Carvalho Costa, Humberto Doriguêtto Gravina, Mauro Shugiro Tada, Dhelio Batista Pereira, Douglas Taylor Golenbock, Lis Ribeiro do Valle Antonelli, and Ricardo T Gazzinelli
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
BACKGROUND:The activation of innate immune responses by Plasmodium vivax results in activation of effector cells and an excessive production of pro-inflammatory cytokines that may culminate in deleterious effects. Here, we examined the activation and function of neutrophils during acute episodes of malaria. MATERIALS AND METHODS:Blood samples were collected from P. vivax-infected patients at admission (day 0) and 30-45 days after treatment with chloroquine and primaquine. Expression of activation markers and cytokine levels produced by highly purified monocytes and neutrophils were measured by the Cytometric Bead Assay. Phagocytic activity, superoxide production, chemotaxis and the presence of G protein-coupled receptor (GRK2) were also evaluated in neutrophils from malaria patients. PRINCIPAL FINDINGS:Both monocytes and neutrophils from P. vivax-infected patients were highly activated. While monocytes were found to be the main source of cytokines in response to TLR ligands, neutrophils showed enhanced phagocytic activity and superoxide production. Interestingly, neutrophils from the malaria patients expressed high levels of GRK2, low levels of CXCR2, and displayed impaired chemotaxis towards IL-8 (CXCL8). CONCLUSION:Activated neutrophils from malaria patients are a poor source of pro-inflammatory cytokines and display reduced chemotactic activity, suggesting a possible mechanism for an enhanced susceptibility to secondary bacterial infection during malaria.
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- 2012
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13. Epidemiological profile of Zika, Dengue and Chikungunya virus infections identified by medical and molecular evaluations in Rondonia, Brazil
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Deusilene Souza Vieira, Miriam Ribas Zambenedetti, Luciana Requião, Ivo Alberto Borghetti, Luciano Kleber de Souza Luna, Alcione de Oliveira dos Santos, Roger Lafontaine Mesquita Taborda, Dhelio Batista Pereira, Marco Aurélio Krieger, Juan Miguel Villalobos Salcedo, and Rita de Cássia Pontello Rampazzo
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Zika ,Chikungunya ,Dengue ,One-step real-time RT-PCR ,Diagnostic ,Arboviruses ,Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
ABSTRACT Several arboviruses have emerged and/or re-emerged in North, Central and South-American countries. Viruses from some regions of Africa and Asia, such as the Zika and Chikungunya virus have been introduced in new continents causing major public health problems. The aim of this study was to investigate the presence of RNA from Zika, Dengue and Chikungunya viruses in symptomatic patients from Rondonia, where the epidemiological profile is still little known, by one-step real-time RT-PCR. The main clinical signs and symtoms were fever (51.2%), headache (78%), chills (6.1%), pruritus (12.2%), exanthema (20.1%), arthralgia (35.3%), myalgia (26.8%) and retro-orbital pain (19.5%). Serum from 164 symptomatic patients were collected and tested for RNA of Zika, Dengue types 1 to 4 and Chikungunya viruses, in addition to antibodies against Dengue NS1 antigen. Direct microscopy for Malaria was also performed. Only ZIKV RNA was detected in 4.3% of the patients, and in the remaining 95.7% of the patients RNA for Zika, Dengue and Chikungunya viruses were not detected. This finding is intriguing as the region has been endemic for Dengue for a long time and more recently for Chikungunya virus as well. The results indicated that medical and molecular parameters obtained were suitable to describe the first report of symptomatic Zika infections in this region. Furthermore, the low rate of detection, compared to clinical signs and symptoms as the solely diagnosis criteria, suggests that molecular assays for detection of viruses or other pathogens that cause similar symptoms should be used and the corresponding diseases could be included in the compulsory notification list.
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14. MEFAS, a hybrid of artesunate-mefloquine active against asexual stages of Plasmodium vivax in field isolates, inhibits malaria transmission
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Carlos Tong Rios, Julia Penna-Coutinho, Jansen Fernandes Medeiros, Nubia Boechat, Antoniana U. Krettli, Dhelio Batista Pereira, Maisa da Silva Araujo, Anna Caroline Campos Aguiar, and Paula Miranda Sá
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Regular article ,Plasmodium vivax ,Plasmodium falciparum ,Artesunate ,Antimalarial ,Drug resistance ,Infectious and parasitic diseases ,RC109-216 ,Drug resistant ,Antimalarials ,chemistry.chemical_compound ,parasitic diseases ,Malaria, Vivax ,medicine ,Gametocyte ,Animals ,Humans ,Pharmacology (medical) ,Malaria, Falciparum ,Artemisinin ,Pharmacology ,biology ,Mefloquine ,medicine.disease ,biology.organism_classification ,Virology ,Malaria ,New drugs ,Infectious Diseases ,chemistry ,Parasitology ,Transmission blocking ,medicine.drug - Abstract
Human malaria continues to be a public health problem and an important cause of morbidity and mortality in the world. Malaria control is achieved through both individual protection against mosquito bites and drug treatment, which is hampered by the spread of Plasmodium falciparum resistance to most antimalarials, including artemisinin derivatives. One of the key pharmacological strategies for controlling malaria is to block transmission of the parasites to their mosquito vectors. Following this rational, MEFAS, a synthetic hybrid salt derived from artesunate (AS) and mefloquine has been previously reported for its activity against asexual P. falciparum parasites in vitro, in addition to a pronounced reduction in the viability of mature gametocytes. Herein, MEFAS was tested against asexual forms of Plasmodium vivax and for its ability to block malaria transmission in Anopheles darlingi mosquitoes in a membrane feeding assay using P. vivax field isolates. MEFAS demonstrated high potency, with a IC50 of 6.5 nM against asexual forms of P. vivax. At 50 μM, MEFAS completely blocked oocyst formation in mosquitoes, regardless of the oocyst number in the control group. At lower doses, MEFAS reduced oocyst prevalence by greater than 20%. At equivalent doses, AS irregularly reduced oocyst formation and caused only slight inhibition of mosquito infections. These results highlight the potential of MEFAS as a novel transmission-blocking molecule, as well as its high blood schizonticidal activity against P. vivax and P. falciparum field isolates, representing a starting point for further development of a new drug with dual antimalarial activity., Graphical abstract Image 1
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- 2021
15. Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors
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Vicky M. Avery, Tomas Yeo, Susan A. Charman, David A. Fidock, Anne-Catrin Uhlemann, Sandra Duffy, Sumanta Dey, Sergio Wittlin, Laura M. Sanz, Rafael Victorio Carvalho Guido, Benigno Crespo, Alisje Churchyard, Atsuko Ochida, Jacquin C. Niles, Anna Caroline Campos Aguiar, Yuichiro Akao, Jake Baum, Karen L. White, Leonardo Lucantoni, Josefine Striepen, Masanori Okaniwa, Angelika Sturm, Dhelio Batista Pereira, Akira Shibata, Koen J. Dechering, David M. Shackleford, Sachel Mok, Benoît Laleu, and Medicines for Malaria Venture
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0301 basic medicine ,Plasmodium ,medicine.medical_specialty ,030106 microbiology ,malaria ,Pharmacology ,PRS ,03 medical and health sciences ,chemistry.chemical_compound ,Medical microbiology ,1108 Medical Microbiology ,medicine ,IC50 ,biology ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,In vitro ,030104 developmental biology ,Infectious Diseases ,chemistry ,ANTIPARASITÁRIOS ,prolyl-tRNA synthetase ,Growth inhibition ,Enantiomer ,Malaria - Abstract
Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1- S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.
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- 2021
16. An open dataset of
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Ishag, Adam, Mohammad Shafiul, Alam, Sisay, Alemu, Chanaki, Amaratunga, Roberto, Amato, Voahangy, Andrianaranjaka, Nicholas M, Anstey, Abraham, Aseffa, Elizabeth, Ashley, Ashenafi, Assefa, Sarah, Auburn, Bridget E, Barber, Alyssa, Barry, Dhelio, Batista Pereira, Jun, Cao, Nguyen Hoang, Chau, Kesinee, Chotivanich, Cindy, Chu, Arjen M, Dondorp, Eleanor, Drury, Diego F, Echeverry, Berhanu, Erko, Fe, Espino, Rick, Fairhurst, Abdul, Faiz, María, Fernanda Villegas, Qi, Gao, Lemu, Golassa, Sonia, Goncalves, Matthew J, Grigg, Yaghoob, Hamedi, Tran Tinh, Hien, Ye, Htut, Kimberly J, Johnson, Nadira, Karunaweera, Wasif, Khan, Srivicha, Krudsood, Dominic P, Kwiatkowski, Marcus, Lacerda, Benedikt, Ley, Pharath, Lim, Yaobao, Liu, Alejandro, Llanos-Cuentas, Chanthap, Lon, Tatiana, Lopera-Mesa, Jutta, Marfurt, Pascal, Michon, Olivo, Miotto, Rezika, Mohammed, Ivo, Mueller, Chayadol, Namaik-Larp, Paul N, Newton, Thuy-Nhien, Nguyen, Francois, Nosten, Rintis, Noviyanti, Zuleima, Pava, Richard D, Pearson, Beyene, Petros, Aung P, Phyo, Ric N, Price, Sasithon, Pukrittayakamee, Awab Ghulam, Rahim, Milijaona, Randrianarivelojosia, Julian C, Rayner, Angela, Rumaseb, Sasha V, Siegel, Victoria J, Simpson, Kamala, Thriemer, Alberto, Tobon-Castano, Hidayat, Trimarsanto, Marcelo, Urbano Ferreira, Ivan D, Vélez, Sonam, Wangchuk, Thomas E, Wellems, Nicholas J, White, Timothy, William, Maria F, Yasnot, and Daniel, Yilma
- Abstract
This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 samples of
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- 2022
17. γδ T cells suppress Plasmodium falciparum blood stage infection by direct killing and phagocytosis
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Ricardo T. Gazzinelli, Jeffrey D. Dvorin, Judy Lieberman, Rafael B. Polidoro, Ângela C. Crespo, Sumit Sen Santara, Zhitao Liang, Dhelio Batista Pereira, Caroline Junqueira, Guilherme Castro, and Sabrina Absalon
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Cytotoxicity, Immunologic ,Male ,0301 basic medicine ,Erythrocytes ,Immunological Synapses ,T-Lymphocytes ,Lymphocyte Activation ,Granzymes ,PLASMODIUM FALCIPARUM ,0302 clinical medicine ,Immunology and Allergy ,Granulysin ,Malaria, Falciparum ,Intraepithelial Lymphocytes ,Cells, Cultured ,Degranulation ,medicine.anatomical_structure ,cytotoxicity ,Female ,Homicide ,Brazil ,butyrophilin ,T cell ,Immunology ,Plasmodium falciparum ,malaria ,Antigens, Protozoan ,Biology ,Article ,Host-Parasite Interactions ,Microbiology ,03 medical and health sciences ,Immune system ,Antigen ,Phagocytosis ,Antigens, CD ,parasitic diseases ,medicine ,Humans ,γδ T cell ,Butyrophilins ,Intracellular parasite ,granulysin ,granzyme ,biology.organism_classification ,antibody-dependent phagocytosis ,030104 developmental biology ,Granzyme ,biology.protein ,Boston ,030215 immunology - Abstract
Activated Vγ9Vδ2 (γδ2) T lymphocytes that sense parasite-produced phosphoantigens are expanded in Plasmodium falciparum–infected patients. Although previous studies suggested that γδ2 T cells help control erythrocytic malaria, whether γδ2 T cells recognize infected red blood cells (iRBCs) was uncertain. Here we show that iRBCs stained for the phosphoantigen sensor butyrophilin 3A1 (BTN3A1). γδ2 T cells formed immune synapses and lysed iRBCs in a contact, phosphoantigen, BTN3A1 and degranulation-dependent manner, killing intracellular parasites. Granulysin released into the synapse lysed iRBCs and delivered death-inducing granzymes to the parasite. All intra-erythrocytic parasites were susceptible, but schizonts were most sensitive. A second protective γδ2 T cell mechanism was identified. In the presence of patient serum, γδ2 T cells phagocytosed and degraded opsonized iRBCs in a CD16-dependent manner, decreasing parasite multiplication. Thus, γδ2 T cells have two ways to control blood-stage malaria–γδ T cell antigen receptor (TCR)-mediated degranulation and phagocytosis of antibody-coated iRBCs. Junqueira et al. show that human γδ T cells control erythrocytic Plasmodium falciparum infection by multiple mechanisms: antibody-dependent phagocytosis, cytotoxic-granule-mediated erythrocyte lysis and direct parasite killing.
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- 2021
18. Epidemiological characterization and sensitivity to traditional antimalarials of Plasmodium spp. isolates from Porto Velho, western Amazon, Brazil
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Daniel Sol Sol de Medeiros, Amália dos Santos Ferreira, Marcinete Latorre Almeida, Norton Rubens Diunior Lucas Pejara Rossi, Raul Afonso Pommer Barbosa, Ana Paula Azevedo dos Santos, Anna Caroline Campos Aguiar, Mauro Shugiro Tada, Dhelio Batista Pereira, and Carolina Bioni Garcia Teles
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General Medicine ,QUÍMICA MÉDICA - Abstract
Objective: To describe the epidemiological profile of patients infected with malaria in Porto Velho and the susceptibility of Plasmodium spp. to different classes of drugs used in current treatment methods. Methods: 708 patients infected with malaria were treated at the Center of Tropical Medicine in Porto Velho, where they answered standard epidemiological questionnaires. Maps were built using place of residence information of 199 infected patients. In chemosensitivity assay, dihydroartemisinin, chloroquine, mefloquine and lumefantrine half maximal inhibitory concentration (IC50) was assessed by schizont maturation assay. Results: A higher prevalence of Plasmodium spp. infection among men, young people, with recurrent events of malaria and residents of urban area can be observed. The most prevalent malaria species was P. vivax followed by P. falciparum. Regarding treatment, it was observed that P. falciparum demonstrated resistance only to chloroquine (CQ) with a median of IC50 (MD of IC50) = 119.8 nM, whereas P. vivax demonstrated sensitivity to all drugs (MD IC50 < 10; 100; 30; and 150 nM for dihydroartemisinin, CQ, mefloquine and lumefantrine, respectively). Conclusion: This study contributes to the understanding of the disease by the city’s public health organs, to Plasmodium chemosensitivity literature and vigilance, and to decision making processes of city officials.
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- 2022
19. Caspase-8 mediates inflammation and disease in rodent malaria
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Larissa M. N. Pereira, Katherine A. Fitzgerald, Caroline Junqueira, Patricia A. Assis, Ricardo T. Gazzinelli, Dario S. Zamboni, Dhelio Batista Pereira, Natalia M. de Araujo, Danielle Fernandes Durso, Egil Lien, Douglas T. Golenbock, and Marco Antonio Ataide
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0301 basic medicine ,Science ,General Physics and Astronomy ,Inflammation ,Systemic inflammation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,medicine ,MALÁRIA ,lcsh:Science ,Caspase ,Multidisciplinary ,biology ,business.industry ,Inflammasome ,General Chemistry ,medicine.disease ,Malaria ,030104 developmental biology ,Cerebral Malaria ,Immunology ,biology.protein ,Infectious diseases ,Tumor necrosis factor alpha ,lcsh:Q ,medicine.symptom ,business ,Parasite host response ,030215 immunology ,medicine.drug - Abstract
Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1β and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease., Inflammasome activation plays a role in malaria pathogenesis, but details aren’t well understood. Here, the authors show that caspase-8 is a central mediator of systemic inflammation in rodent malaria and that monocytes from malaria patients express active caspases-1, -4 and -8.
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- 2020
20. First Observation of Experimental Plasmodium vivax Infection of Three Malaria Vectors from the Brazilian Amazon
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Luis Paulo Costa Carvalho, Jansen Fernandes Medeiros, Luiz Hidelbrando Pereira-da-Silva, Raphael Brum Castro, Maisa da Silva Araujo, Moreno S. Rodrigues, Glaucilene da Silva Costa, Dhelio Batista Pereira, Antonio Marques Pereira Júnior, Alice Oliveira Andrade, and Najara Akira Costa dos Santos
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biology ,Amazon rainforest ,Plasmodium vivax ,Anopheles ,biology.organism_classification ,medicine.disease ,Microbiology ,Virology ,Infectious Diseases ,Vector (epidemiology) ,parasitic diseases ,medicine ,Plasmodium vivax infection ,Parasite hosting ,Malaria vector ,Malaria - Abstract
Although malaria is endemic to the Amazon region, little is known about the susceptibility of potential parasite vectors in Brazil. Assessing the vector susceptibility of Anopheles mosquitoes will ...
- Published
- 2020
21. Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria
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Fe Espino, Chanthap Lon, John J Breton, Marcus V. G. Lacerda, Daniel Yilma, David L. Saunders, Maria F Villegas, Tran Tinh Hien, Pamela L. St. Jean, Srivicha Krudsood, Iván D. Vélez, Gavin C. K. W. Koh, Chayadol S Namaik-Larp, Alejandro Llanos-Cuentas, Stephan Duparc, Justin A. Green, Dhelio Batista Pereira, and Rezika Mohammed
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Male ,0301 basic medicine ,Primaquine ,Tafenoquine ,efficacy ,Plasmodium vivax ,tafenoquine ,030226 pharmacology & pharmacy ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Genetics (clinical) ,pharmacogenetics ,Clinical Trials as Topic ,education.field_of_study ,biology ,Plasmodium vivax malaria ,Middle Aged ,Treatment Outcome ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Aminoquinolines ,Molecular Medicine ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Short Communication ,purl.org/pe-repo/ocde/ford#1.06.03 [https] ,Population ,Polymorphism, Single Nucleotide ,Antimalarials ,Young Adult ,03 medical and health sciences ,Internal medicine ,parasitic diseases ,Malaria, Vivax ,Genetics ,Humans ,In patient ,education ,Molecular Biology ,Retrospective Studies ,Chromosomes, Human, Pair 12 ,business.industry ,medicine.disease ,biology.organism_classification ,Pharmacogenomic Testing ,Clinical trial ,030104 developmental biology ,chemistry ,business ,Pharmacogenetics ,Malaria ,Genome-Wide Association Study ,purl.org/pe-repo/ocde/ford#1.06.07 [https] - Abstract
Supplemental Digital Content is available in the text., Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10−8). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.
- Published
- 2020
22. Parasitological profiling shows 4(1H)-quinolone derivatives as new lead candidates for malaria
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Suzete Maria Almeida, Kangsa Amporndanai, Juliana Calit, Arlene G. Corrêa, Anna Caroline Campos Aguiar, Glaucius Oliva, Juliana Oliveira de Souza, Daniel Y. Bargieri, Camila Lima Zanini, Dhelio Batista Pereira, S. Samar Hasnain, Fabio C. Cruz, Guilherme Eduardo de Souza, Svetlana V. Antonyuk, Everton M. da Silva, and Rafael Victorio Carvalho Guido
- Subjects
Inhibitor ,medicine.drug_class ,Plasmodium falciparum ,4(1H)-Quinolone ,Computational biology ,Biology ,medicine.disease ,Quinolone ,Malaria ,RS1-441 ,PLASMODIUM FALCIPARUM ,Other systems of medicine ,Lead (geology) ,Pharmacy and materia medica ,parasitic diseases ,medicine ,Profiling (information science) ,Plasmodium vivax ,Cytochrome bc1 complex ,RZ201-999 - Abstract
4(1H)-quinolone is an attractive template for antimalarial drug discovery campaigns. Given the current global increase in drug and insecticide resistance, the discovery of new antimalarial drugs is an urgent goal for the fight against malaria. Here, the synthesis and antiplasmodial profiling of a series of 4(1H)-quinolone derivatives are reported. Four compounds showed inhibitory activities in submicromolar range against a panel of sensitive and resistant Plasmodium falciparum strains (IC50s = 0.07–0.48 μM) and neither cytotoxic (SI > 210) nor hemolytic activities were observed. Representative compounds of the series showed slow-acting in vitro inhibition, enhanced inhibitory activities over the later erythrocytic forms of the parasite, and submicromolar activity against the ookinete stage (IC50ook = 0.7 μM). Evaluation of the mechanism of action indicated that the frontrunner, compound 4 (LSPN182), is a potent (IC50Pfbc1 = 0.5 μM) and selective (SI > 120) inhibitor for the cytochrome bc1 complex of P. falciparum. Moreover, the frontrunner exhibited considerable activity against clinical field isolates of both P. falciparum and P. vivax (IC50s of 0.5 and 1.5 μM, respectively), a noticeable synergic inhibitory behavior when combined with the antimalarial proguanil (FICindex < 1), and modest oral efficacy at 50 mg/kg in a mouse model of P. berghei malaria (45% reduction in parasitemia on day 7 postinfection). Hence, the 4(1H)-quinolone derivatives are attractive chemotypes endowed with relevant in vitro, ex vivo, and in vivo activity.
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- 2021
23. A Comprehensive Analysis of the Genetic Diversity of Plasmodium falciparum Histidine-Rich Protein 2 (PfHRP2) in the Brazilian Amazon
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Thamires Oliveira Gasquez Martin, Jaime Louzada, Gabriel Luíz Costa, Maria Eduarda Pereira Mascarenhas, Luzia H. Carvalho, Cor Jesus Fernandes Fontes, Cristiana Ferreira Alves de Brito, Taís Nóbrega de Sousa, Anna Caroline Campos Aguiar, Dhelio Batista Pereira, and Laura Guimarães Fortini
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Microbiology (medical) ,Immunology ,Plasmodium falciparum ,malaria ,Protozoan Proteins ,Antigens, Protozoan ,Microbiology ,Cellular and Infection Microbiology ,parasitic diseases ,medicine ,Parasite hosting ,Humans ,Histidine ,Malaria, Falciparum ,Gene ,Original Research ,Genetics ,Genetic diversity ,biology ,Amazon rainforest ,Diagnostic Tests, Routine ,genetic diversity ,biology.organism_classification ,medicine.disease ,QR1-502 ,pfhrp2 deletion ,Diagnosis of malaria ,Infectious Diseases ,rapid diagnostic test (RDT) ,Nested polymerase chain reaction ,Malaria ,Brazil ,Gene Deletion - Abstract
Early diagnosis and treatment are fundamental to the control and elimination of malaria. In many endemic areas, routine diagnosis is primarily performed microscopically, although rapid diagnostic tests (RDTs) provide a useful point-of-care tool. Most of the commercially available RDTs detect histidine-rich protein 2 (HRP2) of Plasmodium falciparum in the blood of infected individuals. Nonetheless, parasite isolates lacking the pfhrp2 gene are relatively frequent in some endemic regions, thereby hampering the diagnosis of malaria using HRP2-based RDTs. To track the efficacy of RDTs in areas of the Brazilian Amazon, we assessed pfhrp2 deletions in 132 P. falciparum samples collected from four malaria-endemic states in Brazil. Our findings show low to moderate levels of pfhrp2 deletion in different regions of the Brazilian Amazon. Overall, during the period covered by this study (2002-2020), we found that 10% of the P. falciparum isolates were characterized by a pfhrp2 deletion. Notably, however, the presence of pfhrp2-negative isolates has not been translated into a reduction in RDT efficacy, which in part may be explained by the presence of polyclonal infections. A further important finding was the discrepancy in the proportion of pfhrp2 deletions detected using two assessed protocols (conventional PCR versus nested PCR), which reinforces the need to perform a carefully planned laboratory workflow to assess gene deletion. This is the first study to perform a comprehensive analysis of PfHRP2 sequence diversity in Brazilian isolates of P. falciparum. We identified 10 PfHRP2 sequence patterns, which were found to be exclusive of each of the assessed regions. Despite the small number of PfHRP2 sequences available from South America, we found that the PfHRP2 sequences identified in Brazil and neighboring French Guiana show similar sequence patterns. Our findings highlight the importance of continuously monitoring the occurrence and spread of parasites with pfrhp2 deletions, while also taking into account the limitations of PCR-based testing methods associated with accuracy and the complexity of infections.
- Published
- 2021
24. <named-content content-type='genus-species'>Plasmodium vivax</named-content> Infection Alters Mitochondrial Metabolism in Human Monocytes
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Lis Ribeiro do Valle Antonelli, Fabiano Oliveira, A. Ricardo Goncalves, Bruno Coelho Rocha, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Dhelio Batista Pereira, Maria Marta Figueiredo, Suelen Queiroz Diniz, Pedro A C Costa, Mauro Shugiro Tada, and Ricardo T. Gazzinelli
- Subjects
0301 basic medicine ,Male ,Reticulocytes ,mitochondrial metabolism ,Plasmodium vivax ,Gene Expression ,Mitochondrion ,0302 clinical medicine ,Adenosine Triphosphate ,Phagosomes ,P. vivax ,Glycolysis ,chemistry.chemical_classification ,reactive oxygen species ,Middle Aged ,QR1-502 ,Cell biology ,mitochondria ,medicine.anatomical_structure ,SUPERÓXIDO DISMUTASE ,030220 oncology & carcinogenesis ,Female ,monocytes ,Research Article ,Adult ,Adolescent ,SOD2 ,malaria ,Oxidative phosphorylation ,Biology ,Microbiology ,Superoxide dismutase ,03 medical and health sciences ,Young Adult ,Virology ,parasitic diseases ,medicine ,Malaria, Vivax ,Humans ,Aged ,Reactive oxygen species ,Superoxide Dismutase ,Monocyte ,biology.organism_classification ,030104 developmental biology ,chemistry ,biology.protein ,metabolism - Abstract
Monocytes play an important role in the host defense against Plasmodium vivax as the main source of inflammatory cytokines and mitochondrial reactive oxygen species (mROS). Here, we show that monocyte metabolism is altered during human P. vivax malaria, with mitochondria playing a major function in this switch. The process involves a reprograming in which the cells increase glucose uptake and produce ATP via glycolysis instead of oxidative phosphorylation. P. vivax infection results in dysregulated mitochondrial gene expression and in altered membrane potential leading to mROS increase rather than ATP production. When monocytes were incubated with P. vivax-infected reticulocytes, mitochondria colocalized with phagolysosomes containing parasites representing an important source mROS. Importantly, the mitochondrial enzyme superoxide dismutase 2 (SOD2) is simultaneously induced in monocytes from malaria patients. Taken together, the monocyte metabolic reprograming with an increased mROS production may contribute to protective responses against P. vivax while triggering immunomodulatory mechanisms to circumvent tissue damage. IMPORTANCE Plasmodium vivax is the most widely distributed causative agent of human malaria. To achieve parasite control, the human immune system develops a substantial inflammatory response that is also responsible for the symptoms of the disease. Among the cells involved in this response, monocytes play an important role. Here, we show that monocyte metabolism is altered during malaria, with its mitochondria playing a major function in this switch. This change involves a reprograming process in which the cells increase glucose uptake and produce ATP via glycolysis instead of oxidative phosphorylation. The resulting altered mitochondrial membrane potential leads to an increase in mitochondrial reactive oxygen species rather than ATP. These data suggest that agents that change metabolism should be investigated and used with caution during malaria.
- Published
- 2021
25. Evaluation of a point-of-care diagnostic to identify glucose-6-phosphate dehydrogenase deficiency in Brazil
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Pooja Bansil, Wuelton Marcelo Monteiro, Marcus Vg Lacerda, Suellen Clementino Freitas, Marcelo A M Brito, Nicole Advani, Gonzalo J. Domingo, Emily Gerth-Guyette, Marcela Macedo, Aline Soares Moura, Stephanie Zobrist, Dhelio Batista Pereira, Sampa Pal, Eduardo Garbin, and Maria Kahn
- Subjects
Male ,Plasmodium ,Physiology ,RC955-962 ,Biosensing Techniques ,Gastroenterology ,Biochemistry ,Geographical locations ,Medical Conditions ,Arctic medicine. Tropical medicine ,Medicine and Health Sciences ,Child ,Glucose-6-Phosphate Dehydrogenase Deficiency ,Aged, 80 and over ,medicine.diagnostic_test ,Complete blood count ,Anemia ,Hematology ,Middle Aged ,Body Fluids ,Infectious Diseases ,Blood ,Point-of-Care Testing ,Child, Preschool ,Aminoquinolines ,Female ,Public aspects of medicine ,RA1-1270 ,Anatomy ,Brazil ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Blood slide ,Glucosephosphate Dehydrogenase ,Hemolysis ,Antimalarials ,Young Adult ,Internal medicine ,parasitic diseases ,Parasite Groups ,medicine ,Parasitic Diseases ,Malaria, Vivax ,Humans ,Hemoglobin ,Point of care ,Aged ,business.industry ,Public Health, Environmental and Occupational Health ,Hemolytic Anemia ,Biology and Life Sciences ,Proteins ,South America ,medicine.disease ,Tropical Diseases ,Confidence interval ,Malaria ,Capillaries ,Blood Counts ,Cross-Sectional Studies ,Glucosephosphate Dehydrogenase Deficiency ,ROC Curve ,Vivax malaria ,Cardiovascular Anatomy ,Linear Models ,Blood Vessels ,Parasitology ,People and places ,business ,Apicomplexa ,Glucose-6-phosphate dehydrogenase deficiency - Abstract
Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency, prevalent in many malaria-endemic countries. G6PD-deficient individuals are susceptible to hemolysis during oxidative stress, which can occur from exposure to certain medications, including 8-aminoquinolines used to treat Plasmodium vivax malaria. Accordingly, access to point-of-care (POC) G6PD testing in Brazil is critical for safe treatment of P. vivax malaria. Methodology/Principal findings This study evaluated the performance of the semi-quantitative, POC STANDARD G6PD Test (SD Biosensor, Republic of Korea). Participants were recruited at clinics and through an enriched sample in Manaus and Porto Velho, Brazil. G6PD and hemoglobin measurements were obtained from capillary samples at the POC using the STANDARD and HemoCue 201+ (HemoCue AB, Sweden) tests. A thick blood slide was prepared for malaria microscopy. At the laboratories, the STANDARD and HemoCue tests were repeated on venous samples and a quantitative spectrophotometric G6PD reference assay was performed (Pointe Scientific, Canton, MI). G6PD was also assessed by fluorescent spot test. In Manaus, a complete blood count was performed. Samples were analyzed from 1,736 participants. In comparison to spectrophotometry, the STANDARD G6PD Test performed equivalently in determining G6PD status in venous and capillary specimens under varied operating temperatures. Using the manufacturer-recommended reference value thresholds, the test’s sensitivity at the, Author summary G6PD deficiency affects an estimated 500 million people worldwide and is prevalent in many malaria-endemic settings. People with G6PD deficiency are at risk of hemolysis when exposed to certain medications, including 8-aminoquinoline drugs used to treat Plasmodium vivax malaria. Increased access to testing for G6PD deficiency at or near the point of care is critical for expanding the safe treatment of P. vivax malaria. In this study, we aimed to evaluate the performance of a point-of-care, semi-quantitative test for G6PD deficiency, the STANDARD G6PD Test, in a malaria-endemic setting in Brazil. The test was evaluated on both capillary and venous blood samples across a broad range of operating temperatures. The findings show that the STANDARD G6PD Test performed equivalently to the reference test in its ability to diagnose G6PD deficiency at the point of care. The STANDARD G6PD Test is a promising tool to aid in detecting G6PD deficiency at the point of care in Brazil.
- Published
- 2021
26. Point-of-Care Strategies Applied to Malaria Diagnosis
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Angelina Moraes Silva, Anna Caroline Campos Aguiar, Dhelio Batista Pereira, and Alexandre Dias Tavares Costa
- Subjects
0303 health sciences ,medicine.medical_specialty ,business.industry ,InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL ,030231 tropical medicine ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,business ,Intensive care medicine ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Malaria ,030304 developmental biology ,Point of care - Abstract
Rapid and specific diagnosis of malaria remains one of the main strategies to fight the disease. The diagnosis is made primarily by the simple and low-cost thick drop technique, considered the gold standard test. However, the requirement for good quality microscopes and well-trained personnel often lead to inaccurate diagnosis, especially in cases of mixed infections or low parasitemia. Although PCR-based tests can help in these situations, this technique requires large and sensitive equipments, being unsuitable for point of care (POC) settings. A myriad of POC diagnostic tests have being developed in the last years, relying on molecular methods but also on novel strategies. New platforms, miniaturization techniques, and multiplexing possibilities promise great potential to improve disease diagnostics through fast and accurate detection of cases, even at remote places. Here, we will address the main POC strategies developed for the diagnosis of malaria, highlighting their strengths and weakness as POC applications.
- Published
- 2021
27. Usability of a point-of-care diagnostic to identify glucose-6-phosphate dehydrogenase deficiency: a multi-country assessment of test label comprehension and results interpretation
- Author
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Dhelio Batista Pereira, Stephanie Zobrist, Marcela Macedo, Eduardo Garbin, Gonzalo J. Domingo, Arunansu Talukdar, Sampa Pal, Marcelo A M Brito, Santasabuj Das, Marcus V. G. Lacerda, Wondimagegn Adissu, Abhijit Sharma, Emily Gerth-Guyette, and Daniel Yilma
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Inservice Training ,Computer science ,Point-of-care diagnostics ,Point-of-care testing ,Usability ,RC955-962 ,030231 tropical medicine ,Applied psychology ,India ,Infectious and parasitic diseases ,RC109-216 ,Glucosephosphate Dehydrogenase ,Product Labeling ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,G6PD deficiency ,Arctic medicine. Tropical medicine ,parasitic diseases ,User proficiency ,Humans ,030212 general & internal medicine ,Product (category theory) ,User training ,Product design specification ,Malaria diagnosis ,End user ,business.industry ,Research ,Malaria ,Test (assessment) ,Comprehension ,Glucosephosphate Dehydrogenase Deficiency ,Infectious Diseases ,Workflow ,Point-of-Care Testing ,Label comprehension study ,Parasitology ,Clinical Competence ,Ethiopia ,business ,Brazil - Abstract
Background Point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing has the potential to make the use of radical treatment for vivax malaria safer and more effective. Widespread use of G6PD tests as part of malaria case management has been limited, in part due to due concerns regarding product usability, user training, and supervision. This study seeks to assess how well end users can understand the Standard™ G6PD Test (SD Biosensor, Suwon, South Korea) workflow, result output, and label after training. This will ultimately help inform test registration and introduction. Methods Potential G6PD test users who provide malaria case management at three sites in Brazil, Ethiopia, and India were trained on the use of the SD Biosensor Standard G6PD Test and assessed based on their ability to understand the test workflow and interpret results. The assessment was done through a questionnaire, designed to assess product usability against key technical product specifications and fulfill regulatory evidence requirements. Any participant who obtained 85% or above correct responses to the questionnaire was considered to adequately comprehend how to use and interpret the test. Results Forty-five participants, including malaria microscopists, laboratory staff, nurses, and community health workers took part in the study. Seventy-eight percent of all participants in the study (35/45) obtained passing scores on the assessment with minimal training. Responses to the multiple-choice questions indicate that most participants understood well the test intended use, safety claims, and warnings. The greatest source of error regarding the test was around the correct operating temperature. Most test results were also read and interpreted correctly, with the haemoglobin measurement being a more problematic output to interpret than the G6PD measurement. Conclusions These data results show how a standardized tool can be used to assess a user’s ability to run a point-of-care diagnostic and interpret results. When applied to the SD Biosensor Standard G6PD Test, this tool demonstrates that a range of users across multiple contexts can use the test and suggests improvements to the test instructions and training that can improve product usability, increase user comprehension, and ultimately contribute to more widespread effective use of point-of-care G6PD tests. Trial registration: NCT04033640
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- 2021
28. Description of malaria vectors (Diptera: Culicidae) in two agricultural settlements in the Western Brazilian Amazon
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Jansen Fernandes Medeiros, Alessandra da Silva Bastos, Najara Akira Costa dos Santos, Felipe Neves Magi, Maisa da Silva Araujo, Raphael Brum Castro, Dhelio Batista Pereira, Moreno S. Rodrigues, Alice Oliveira Andrade, and Isabelle Sousa de Araujo
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Plasmodium ,RC955-962 ,Disease transmission ,Zoology ,Mosquito Vectors ,law.invention ,law ,Arctic medicine. Tropical medicine ,Human settlement ,parasitic diseases ,Anopheles ,medicine ,Animals ,Humans ,Colonization ,biology ,Amazon rainforest ,biology.organism_classification ,medicine.disease ,Rural communities ,Malaria ,Geography ,Transmission (mechanics) ,Original Article ,Species richness ,Rural area ,Brazil - Abstract
The majority of malaria cases in South America occur in rural areas of the Amazon region. Although these areas have a significant impact on malaria cases, few entomological studies have been carried out there. This study aimed to describe entomological parameters in settlements in Rondonia State, Brazil. Collections of anopheles were carried out using the Protected Human Attraction Technique (PHAT). The risk and the potential for malaria transmission were assessed using the human biting rate (HBR), the sporozoite rate (SR) and the entomological inoculation rate (EIR). The results confirmed that Nyssorhynchus darlingi is the predominant species in the two studied locations. Although settlement in the two study sites has occurred at different times, the species richness found was low, showing that environmental changes caused by anthropological actions have probably favor the adaptation of Ny. darlingi species. From the total of 615 anopheline mosquitoes assessed, seven (1.1%) were positive for Plasmodium sp. infections. The EIR revealed that Ny. darlingi contributes to malaria transmission in both locations, as it was responsible for 0.05 infectious bites in humans at night in the old settlement and 0.02 in the recent occupation. In the two study sites, the biting occurred more frequently at dusk. Nyssorhynchus darlingi was prevalent in areas of recent colonization but, even when present in a low density, this species could maintain the transmission of malaria in the older settlement. The entomological information obtained in this study is important and may aid the selection of vector control actions in these locations.
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- 2021
29. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183
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Julie M. J. Verhoef, Rosemary Rochford, Philip J. Rosenthal, Graham P. Trevitt, Patrick K Tumwebaze, Barcelo C, Manuel Llinás, Jacquin C. Niles, Koen J. Dechering, Henderson R, Roger Bonnert, Dhelio Batista Pereira, Anna Caroline Campos Aguiar, Huijs T, Judith M. Bolscher, David A. Fidock, Tomas Yeo, Robert W. Sauerwein, Pasaje Cfa, Jake Baum, Patrick A. M. Jansen, Brice Campo, Roland A. Cooper, Taco W. A. Kooij, de Vries Le, María Belén Jiménez-Díaz, Iñigo Angulo-Barturen, Francisco J. Gamo, Josefine Striepen, Pedro H. H. Hermkens, Sergio Wittlin, Rafael Victorio Carvalho Guido, Kelly Rubiano, Justin Munro, Fernandez Bc, Laura M. Sanz, Karin M. J. Koolen, J. Schalkwijk, and Alisje Churchyard
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biology ,business.industry ,medicine.drug_class ,Anopheles ,Drug resistance ,Pharmacology ,medicine.disease ,biology.organism_classification ,Antimetabolite ,Oral administration ,In vivo ,parasitic diseases ,Humanized mouse ,Medicine ,business ,Mode of action ,Malaria - Abstract
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic – pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.
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- 2021
30. Single-Dose Tafenoquine to Prevent Relapse ofPlasmodium vivaxMalaria
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Kalehiwot M Wubie, Marcus V. G. Lacerda, Françoise Brand, Kim Fletcher, Alemseged Abdissa, Nillawan Buathong, Elizabeth Hardaker, Harald Noedl, Victoria M Rousell, Ermias Diro, Jörg-Peter Kleim, Monica R. F. Costa, Brian Angus, John J Breton, Alejandro Llanos-Cuentas, Lynda Kellam, Reginaldo Z Mia, Marcelo A M Brito, Martin Casapia, Hans-Peter Beck, Fe Espino, Raul Chuquiyauri, Wuelton Marcelo Monteiro, Rezika Mohammed, Donna D Clover, Fernando Val, Sisay Getie, Justin A. Green, Dhelio Batista Pereira, Daniel Yilma, Stephan Duparc, Mauro Shugiro Tada, Cherinet Abebe, Ahmed Zeynudin, Siôn W. Jones, Khadeeja Mohamed, David L. Saunders, Cletus O Ugwuegbulam, Gavin C. K. W. Koh, Chanthap Lon, and Srivicha Krudsood
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Male ,double blind procedure ,drug safety ,Primaquine ,Kaplan Meier method ,Tafenoquine ,Philippines ,Plasmodium vivax ,Kaplan-Meier Estimate ,tafenoquine ,Parasitemia ,aminoquinoline derivative ,030204 cardiovascular system & hematology ,chloroquine ,Hemoglobins ,chemistry.chemical_compound ,0302 clinical medicine ,Chloroquine ,Peru ,Secondary Prevention ,030212 general & internal medicine ,Antimalarial Agent ,disease free survival ,methemoglobin ,relapse ,glucose 6 phosphate dehydrogenase ,parasite clearance ,biology ,adult ,Plasmodium vivax malaria ,single drug dose ,food and beverages ,clinical trial ,General Medicine ,Thailand ,enzyme activity ,Intention to Treat Analysis ,G6PD protein, human ,female ,Cytochrome P-450 CYP2D6 ,priority journal ,retinal hypopigmentation ,Aminoquinolines ,disease severity ,Drug Therapy, Combination ,Cambodia ,hypopigmentation ,Brazil ,recurrence risk ,medicine.drug ,combination drug therapy ,Adolescent ,hematocrit ,Glucosephosphate Dehydrogenase ,Disease-Free Survival ,Article ,Antimalarials ,03 medical and health sciences ,Pharmacotherapy ,Double-Blind Method ,retina disease ,parasitic diseases ,Malaria, Vivax ,medicine ,Humans ,controlled study ,human ,procedures ,cytochrome P450 2D6 ,dizziness ,keratopathy ,treatment duration ,phase 3 clinical trial ,antimalarial agent ,isolation and purification ,business.industry ,statistical model ,fungi ,hemoglobin ,medicine.disease ,biology.organism_classification ,major clinical study ,Virology ,purl.org/pe-repo/ocde/ford#3.02.00 [https] ,phase 2 clinical trial ,Logistic Models ,multicenter study ,chemistry ,randomized controlled trial ,placebo ,Ethiopia ,business ,metabolism ,Malaria - Abstract
Background Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed “radical cure”). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. Methods This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to Results In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P Conclusions Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167. opens in new tab.)
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- 2019
31. Investigation of Malaria Vectors (Diptera: Culicidae) in Agricultural Settlements in the Amazon Region of Brazil
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Jansen Fernandes Medeiros, Maisa da Silva Araujo, Moreno S. Rodrigues, Raphael Brum Castro, Isabelle Sousa de Araujo, Alessandra da Silva Bastos, Dhelio Batista Pereira, Felipe Neves Magi, Alice Oliveira Andrade, and Najara Akira Costa dos Santos
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Geography ,Amazon rainforest ,Agroforestry ,Agriculture ,business.industry ,Human settlement ,parasitic diseases ,Malaria vector ,business - Abstract
Background: Environmental changes resulting from the urbanization process represent a challenge for malaria control. The majority of malaria cases in South America occur in rural areas, areas of recent occupation, mining and indigenous areas of the Amazon region. Although these areas have a significant impact on malaria cases, few entomological studies have been carried out in areas of recent occupation. This study aimed to describe the density, natural infection rate and hematophagic behavior of anopheline species in two settlements in the state of Rondonia, Brazil in order to understand how malaria transmission occurs in areas that have been settled at different times.Methods: An area of recent occupation, denominated Acampamento Fortaleza (AF), and an old settlement, denominated Projeto de Assentamento Florestal Jequitibá (PAFJ), were studied. Peridomicile collections of anopheles were carried out using the Protected Human Attraction Technique (PHAT). The risk and potential for malaria transmission were assessed using the human biting rate (HBR), sporozoite rate (SR) and the entomological inoculation rate (EIR).Results: The results confirmed that Nyssorhynchus darlingi, the main vector responsible for the transmission of malaria in the state of Rondônia, is the predominant species in the two studied locations. Although settlement of the two study sites has occurred at different times, the species richness found was low, showing that the environmental changes caused by anthropological actions probably favor the adaptation of the Ny. darlingi species. Of the 615 anopheline mosquitoes assessed, 7 (1.1%) were positive for Plasmodium infections. The EIR revealed that Ny. darlingi contributes to the transmission of malaria in both locations, since it was responsible for 0.41 infectious bites in humans at night in PAFJ and 0.16 in AF. In the two study sites, the biting occurred more frequently at dusk.Conclusions: Ny. darlingi is the principal vector found in the studied locations. Its prevalence occurs in areas of recent colonization but, even when present in a low density, this species could maintain transmission of malaria in an older settlement. The entomological information obtained in this study is important and may aid the selection of vector control actions in these locations that are considered as having a high risk of malaria transmission.
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- 2021
32. A distinct fingerprint of inflammatory mediators and miRNAs inPlasmodium vivaxsevere thrombocytopenia
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Luiz F. F. Guimarães, Ibrahim Hawwari, Luzia H. Carvalho, Matheus de Souza Gomes, Cor Jesus Fernandes Fontes, Taís Nóbrega de Sousa, Marina L. S. Santos, Bernardo S. Franklin, Laurence Rodrigues do Amaral, Roney S. Coimbra, and Dhelio Batista Pereira
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biology ,business.industry ,medicine.medical_treatment ,Plasmodium vivax ,CCL2 ,medicine.disease ,biology.organism_classification ,Proteomics ,Cytokine ,microRNA ,Immunology ,medicine ,CXCL10 ,Signal transduction ,business ,Malaria - Abstract
BackgroundSevere thrombocytopenia can be a determinant factor in the morbidity ofPlasmodium vivax(Pv), the most widespread human malaria. Although immune mechanisms may drivePv-induced severe thrombocytopenia (PvST), the current data on the cytokine landscape in PvST is scarce, and often conflicting. The analysis of the bidirectional circuit of inflammatory mediators and miRNAs would lead to a better understanding of the mechanisms underlying PvST.MethodsWe combined Luminex proteomics, NanoString miRNA quantification, and machine learning, to evaluate an extensive array of plasma mediators in uncomplicatedPvpatients, whose blood platelet counts varied from reference values to PvST.ResultsUnsupervised clustering analysis identified PvST-linked signatures comprised of both inflammatory (CXCL10, CCL4, and IL-18) and regulatory (IL-10, IL-1Ra, HGF) mediators. As part of PvST signatures, IL-6 and IL-8 were critical to discriminatePvsubgroups, while CCL2 and IFN-γ from healthy controls. Supervised machine learning spotlighted IL-10 inPv-mediated thrombocytopenia, and provided evidence for a potential signaling route involving IL-8 and HGF. Finally, we identified a set of miRNAs capable of modulating these signaling pathways.ConclusionsThe results place IL-10 and IL-8/HGF in the center of PvST and propose investigating these signaling pathways across the spectrum of malaria infections.
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- 2020
33. A Multistage Formulation Based on Full-Length CSP and AMA-1 Ectodomain of Plasmodium vivax Induces High Antibody Titers and T-cells and Partially Protects Mice Challenged with a Transgenic Plasmodium berghei Parasite
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Luciana Campos Lima, Katia Sanches Françoso, Eduardo Aliprandini, Rogerio Amino, Rodolfo F. Marques, Anna Caroline Campos Aguiar, Laurent Rénia, Irene S. Soares, Tarsila Mendes de Camargo, Alba Marina Gimenez, Dhelio Batista Pereira, University of São Paulo (USP), Infection et Immunité paludéennes - Malaria Infection and Immunity, Institut Pasteur [Paris], Centro de Pesquisas em Medicina Tropical [Porto Velho, Brazil] (CEPEM), Singapore Immunology Network (SIgN), This study was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grants 2012/13032-5, 2014/18102-7, and 2018/17364-9), the National Institute for Vaccine Development and Technology (CNPq—INCTV), Institut Pasteur—Paris, and the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant ANR-10-LABX-62-IBEID). L.C.L., A.M.G., and T.M.C. were recipients of fellowship from FAPESP, R.F.M. from Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior, and I.S.S. from CNPq., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Universidade de São Paulo = University of São Paulo (USP), and Institut Pasteur [Paris] (IP)
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0301 basic medicine ,Microbiology (medical) ,malaria vaccine ,[SDV]Life Sciences [q-bio] ,030231 tropical medicine ,Plasmodium vivax ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Virology ,parasitic diseases ,Plasmodium berghei ,Apical membrane antigen 1 ,lcsh:QH301-705.5 ,biology ,Malaria vaccine ,Antibody titer ,ANTIMALÁRICOS ,biology.organism_classification ,3. Good health ,Circumsporozoite protein ,030104 developmental biology ,lcsh:Biology (General) ,apical membrane antigen 1 ,biology.protein ,Antibody ,circumsporozoite protein ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Infections with Plasmodium vivax are predominant in the Americas, representing 75% of malaria cases. Previously perceived as benign, malaria vivax is, in fact, a highly debilitating and economically important disease. Considering the high complexity of the malaria parasite life cycle, it has been hypothesized that an effective vaccine formulation against Plasmodium should contain multiple antigens expressed in different parasite stages. Based on that, we analyzed a recombinant P. vivax vaccine formulation mixing the apical membrane antigen 1 ectodomain (PvAMA-1) and a full-length circumsporozoite protein (PvCSP-AllFL) previously studied by our group, which elicits a potent antibody response in mice. Genetically distinct strains of mice (C57BL/6 and BALB/c) were immunized with the proteins, alone or in combination, in the presence of poly(I:C) adjuvant, a TLR3 agonist. In C57BL/6, high-antibody titers were induced against PvAMA-1 and the three PvCSP variants (VK210, VK247, and P. vivax-like). Meanwhile, mixing PvAMA-1 with PvCSP-AllFL had no impact on total IgG antibody titers, which were long-lasting. Moreover, antibodies from immunized mice recognized VK210 sporozoites and blood-stage parasites by immunofluorescence assay. However, in the BALB/c model, the antibody response against PvCSP-AllFL was relatively low. PvAMA-1-specific CD3+CD4+ and CD3+CD8+ T-cell responses were observed in C57BL/6 mice, and the cellular response was impaired by PvCSP-AllFL combination. More relevant, the multistage vaccine formulation provided partial protection in mice challenged with a transgenic Plasmodium berghei sporozoite expressing the homologous PvCSP protein.
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- 2020
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34. Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax–infected reticulocytes
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Ricardo T. Gazzinelli, Camila R. R. Barbosa, Caroline Junqueira, Sumit Sen Santara, Farokh Dotiwala, Lis Ribeiro do Valle Antonelli, Pedro A C Costa, Guilherme Castro, Dhelio Batista Pereira, Andréa Teixeira-Carvalho, Judy Lieberman, and Rafael Polidoro Alves Barbosa
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0301 basic medicine ,biology ,Intracellular parasite ,T cell ,Plasmodium vivax ,General Medicine ,biology.organism_classification ,Virology ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Granzyme ,Antigen ,Perforin ,parasitic diseases ,biology.protein ,medicine ,Cytotoxic T cell ,Granulysin ,030215 immunology - Abstract
Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2. The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4. Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells. Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6. Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite. Cytotoxic CD8+ T cells were thought to have no role against Plasmodium spp. blood stages because red blood cells generally do not express human leukocyte antigen class I7. However, P. vivax infects reticulocytes that retain the protein translation machinery. Here we show that P. vivax–infected reticulocytes express human leukocyte antigen class I. Infected patient circulating CD8+ T cells highly express cytotoxic proteins and recognize and form immunological synapses with P. vivax–infected reticulocytes in a human leukocyte antigen–dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion. P. vivax–infected reticulocytes and parasite killing is perforin independent, but depends on granulysin, which generally efficiently forms pores only in microbial membranes8. We find that P. vivax depletes cholesterol from the P. vivax–infected reticulocyte cell membrane, rendering it granulysin-susceptible. This unexpected T cell defense might be mobilized to improve P. vivax vaccine efficacy. T cells kill blood-stage Plasmodium vivax, providing a rationale for the development of a T cell vaccine against this parasite.
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- 2018
35. The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis
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Timothy M. E. Davis, François Nosten, Ayodhia Pitaloka Pasaribu, Kartini Lidia, Harin Karunajeewa, Prabin Dahal, Nicholas M. Anstey, J. Kevin Baird, Brioni R. Moore, Ishag Adam, Arjen M. Dondorp, Kasia Stepniewska, Julie A. Simpson, Bridget E. Barber, Carol Hopkins Sibley, Tesfay Abreha, Robert J. Commons, Ric N. Price, Kamala Thriemer, Charles J. Woodrow, André Daher, Guy E. Thwaites, Dhelio Batista Pereira, Matthew J. Grigg, Georgina S Humphreys, Ivo Mueller, Moses Laman, Tran Tinh Hien, Inge Sutanto, Ashenafi Assefa, Philippe J Guerin, Ghulam Rahim Awab, Jeanne Rini Poespoprodjo, Jimee Hwang, Timothy William, Cindy S. Chu, Nicholas J. White, and Aung Pyae Phyo
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Plasmodium ,Primaquine ,Artemether/lumefantrine ,Plasmodium vivax ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,qv_258 ,Mathematical and Statistical Techniques ,0302 clinical medicine ,Dihydroartemisinin/piperaquine ,Recurrence ,Medicine and Health Sciences ,qv_256 ,030212 general & internal medicine ,Artemether ,biology ,Pharmaceutics ,Statistics ,Artesunate/amodiaquine ,Drugs ,Chloroquine ,General Medicine ,Research Assessment ,Metaanalysis ,Artemisinins ,3. Good health ,Treatment Outcome ,Physical Sciences ,Quinolines ,Medicine ,Research Article ,medicine.drug ,Risk ,medicine.medical_specialty ,Systematic Reviews ,Research and Analysis Methods ,Lumefantrine ,Antimalarials ,03 medical and health sciences ,Dose Prediction Methods ,Piperaquine ,Internal medicine ,Parasite Groups ,Malaria, Vivax ,Parasitic Diseases ,medicine ,Humans ,Statistical Methods ,Pharmacology ,business.industry ,Artemether, Lumefantrine Drug Combination ,Biology and Life Sciences ,Tropical Diseases ,biology.organism_classification ,Malaria ,wc_750 ,chemistry ,qx_135 ,Parasitology ,business ,Apicomplexa ,Mathematics - Abstract
Background Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Methods and findings Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. Conclusions In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis., In this systematic review and individual patient data meta-analysis, Robert Commons and colleagues compare the clinical efficacy of different artemisinin-based combination therapies for treating Plasmodium vivax malaria., Author summary Why was this study done? The susceptibility of Plasmodium vivax to chloroquine is decreasing in many malaria-endemic locations. Artemisinin-based combination therapies (ACTs) are recommended in areas of emerging chloroquine resistance; however, the optimal ACT is not clear. Knowledge of the comparative advantages and disadvantages of different ACTs will help guide national policy makers. What did the researchers do and find? Following a systematic review, individual data from 2,017 patients were pooled from 19 studies undertaken between January 1, 2000, and January 31, 2018. Cox regression analysis showed that the risk of recurrence at day 42 was 12-fold greater following treatment with artemether-lumefantrine (AL) alone compared with dihydroartemisinin-piperaquine (DP), although by day 63 the risk of recurrence following DP was also high. For every 5-mg/kg increase in the dose of piperaquine, the risk of recurrence at day 42 fell by 37%. A delay in the time to symptomatic recurrence was associated with an increase in haemoglobin. Coadministration with primaquine reduced the risk of recurrence at day 42 after AL by 80% and at day 63 after DP by 92%. What do these findings mean? There is a high risk of recurrence following AL or DP unless they are combined with primaquine. Compared with AL, patients treated with DP have a reduced risk of early P. vivax recurrence. Delaying the time to recurrence was associated with greater haematological recovery, and this has potential to prevent morbidity related to multiple rapid recurrences by preventing a cumulative risk of anaemia.
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- 2019
36. Naturally Acquired Antibody Response to Malaria Transmission Blocking Vaccine Candidate Pvs230 Domain 1
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Ricardo Toshio Fujiwara, Niraj H. Tolia, Nichole D. Salinas, Dhelio Batista Pereira, Bergeline C. Nguemwo Tentokam, Lilian Lacerda Bueno, Sokunthea Sreng, Nicholas J. MacDonald, Chanaki Amaratunga, Camila H. Coelho, Seila Suon, Nada Alani, David L. Narum, Jennifer Kwan, and Patrick E. Duffy
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Adult ,Male ,Plasmodium vivax ,Immunology ,Plasmodium falciparum ,malaria ,Antibodies, Protozoan ,Antigens, Protozoan ,Serology ,03 medical and health sciences ,Hemoglobins ,0302 clinical medicine ,Immune system ,Antigen ,parasitic diseases ,Malaria Vaccines ,medicine ,Gametocyte ,Malaria, Vivax ,Immunology and Allergy ,Humans ,Original Research ,Aged ,Aged, 80 and over ,biology ,Pvs230 ,Age Factors ,Middle Aged ,biology.organism_classification ,medicine.disease ,3. Good health ,seroreactivity ,Titer ,030104 developmental biology ,transmission-blocking vaccine ,Immunoglobulin G ,biology.protein ,Female ,Antibody ,lcsh:RC581-607 ,Malaria ,030215 immunology - Abstract
Plasmodium vivaxmalaria incidence has increased in Latin America and Asia and is responsible for nearly 74.1% of malaria cases in Latin America. Immune responses toP. vivaxare less well characterized than those toP. falciparum, partly becauseP. vivaxis more difficult to cultivate in the laboratory. While antibodies are known to play an important role inP. vivaxdisease control, few studies have evaluated responses toP. vivaxsexual stage antigens. We collected sera or plasma samples fromP. vivax-infected subjects from Brazil (n= 70) and Cambodia (n= 79) to assess antibody responses to domain 1 of the gametocyte/gamete stage protein Pvs230 (Pvs230D1M). We found that 27.1% (19/70) and 26.6% (21/79) of subjects from Brazil and Cambodia, respectively, presented with detectable antibody responses to Pvs230D1M antigen. The most frequent subclasses elicited in response to Pvs230D1M were IgG1 and IgG3. Although age did not correlate significantly with Pvs230D1M antibody levels overall, we observed significant differences between age strata. Hemoglobin concentration inversely correlated with Pvs230D1M antibody levels in Brazil, but not in Cambodia. Additionally, we analyzed the antibody response against Pfs230D1M, theP. falciparumortholog of Pvs230D1M. We detected antibodies to Pfs230D1M in 7.2 and 16.5% of Brazilian and CambodianP. vivax-infected subjects. Depletion of Pvs230D1M IgG did not impair the response to Pfs230D1M, suggesting pre-exposure toP. falciparum, or co-infection. We also analyzed IgG responses to sporozoite protein PvCSP (11.4 and 41.8% in Brazil and Cambodia, respectively) and to merozoite protein PvDBP-RII (67.1 and 48.1% in Brazil and Cambodia, respectively), whose titers also inversely correlated with hemoglobin concentration only in Brazil. These data establish patterns of seroreactivity to sexual stage Pvs230D1M and show similar antibody responses amongP. vivax-infected subjects from regions of differing transmission intensity in Brazil and Cambodia.
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- 2019
37. Plasmodium vivax Infection Impairs Regulatory T-Cell Suppressive Function During Acute Malaria
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Dhelio Batista Pereira, Pedro A C Costa, Lis Ribeiro do Valle Antonelli, Andréa Teixeira-Carvalho, Kevin J. Maloy, Maria Marta Figueiredo, Ana P M M Peixoto, Ricardo T. Gazzinelli, Mauro Shugiro Tada, and Suelen Queiroz Diniz
- Subjects
Adult ,Male ,0301 basic medicine ,Reticulocytes ,Regulatory T cell ,medicine.medical_treatment ,Plasmodium vivax ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Immunophenotyping ,Proinflammatory cytokine ,Young Adult ,Major Articles and Brief Reports ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,parasitic diseases ,Malaria, Vivax ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Transcription factor ,Cell Proliferation ,FOXP3 ,hemic and immune systems ,Middle Aged ,biology.organism_classification ,030104 developmental biology ,Infectious Diseases ,Cytokine ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology ,Cytokines ,Female ,030215 immunology - Abstract
The balance between pro- and antiinflammatory mechanisms is essential to limit immune-mediated pathology, and CD4(+) forkhead box P3 (Foxp3(+)) regulatory T cells (Treg) play an important role in this process. The expression of inhibitory receptors regulates cytokine production by Plasmodium vivax-specific T cells. Our goal was to assess the induction of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen (CTLA-4) on Treg during malaria and to evaluate their function. We found that P. vivax infection triggered an increase in circulating Treg and their expression of CTLA-4 and PD-1. Functional analysis demonstrated that Treg from malaria patients had impaired suppressive ability and PD-1(+)Treg displayed lower levels of Foxp3 and Helios, but had higher frequencies of T-box transcription factor(+) and interferon-gamma(+) cells than PD-1(−)Treg. Thus malaria infection alters the function of circulating Treg by triggering increased expression of PD-1 on Treg that is associated with decreased regulatory function and increased proinflammatory characteristics.
- Published
- 2018
38. Uso de terapias naturais durante o tratamento da infecção de plasmodium vivax no município de Porto Velho-RO
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Myrna Gelle Oliveira, Onassis Boeri de Castro, Grazyelle Linhares Leite, Simone Custódio Diniz, André Ramalho, Alyne Ribeiro de Souza, Dhelio Batista Pereira, Raida Alves Lima, Yasmin Dene, and Letícia Helena de Carvalho
- Subjects
General Medicine - Published
- 2018
39. New highly antigenic linear B cell epitope peptides from PvAMA-1 as potential vaccine candidates
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Isabella Carvalho de Azevedo, Anderson C. dos Santos, Vanessa Gomes Fraga, Raianna F. Fantin, Camila Lopes, Ricardo Toshio Fujiwara, Lilian Lacerda Bueno, Dhelio Batista Pereira, Marcela M. de Oliveira, Daniela C. Bartholomeu, Francisco Pereira Lobo, and João Luís Reis-Cunha
- Subjects
Male ,Plasmodium ,Physiology ,Protozoan Proteins ,Biochemistry ,Protein Structure, Secondary ,Geographical locations ,Epitope ,Medical Conditions ,Immune Physiology ,Medicine and Health Sciences ,Enzyme-Linked Immunoassays ,Immune Response ,Vaccines ,Immune System Proteins ,Multidisciplinary ,biology ,Immunogenicity ,Middle Aged ,Acquired immune system ,Infectious Diseases ,Medicine ,Epitopes, B-Lymphocyte ,Female ,Antibody ,Brazil ,Research Article ,Adult ,Antigenicity ,Infectious Disease Control ,Science ,Immunology ,Antigens, Protozoan ,Research and Analysis Methods ,Antibodies ,Immune system ,Antigen ,Malaria Vaccines ,Parasite Groups ,Malaria, Vivax ,Parasitic Diseases ,Humans ,Amino Acid Sequence ,Antigens ,Immunoassays ,Immunodominant Epitopes ,Membrane Proteins ,Biology and Life Sciences ,Proteins ,South America ,Apical membrane ,Tropical Diseases ,Virology ,Malaria ,Case-Control Studies ,Immunoglobulin G ,Antibody Formation ,Immunologic Techniques ,biology.protein ,Parasitology ,People and places ,Peptides ,Plasmodium vivax ,Apicomplexa - Abstract
Peptide-based vaccines have demonstrated to be an important way to induce long-lived immune responses and, therefore, a promising strategy in the rational of vaccine development. As to malaria, among the classic vaccine targets, the Apical membrane antigen (AMA-1) was proven to have important B cell epitopes that can induce specific immune response and, hence, became key players for a vaccine approach. The peptides selection was carried out using a bioinformatic approach based on Hidden Markov Models profiles of known antigens and propensity scale methods based on hydrophilicity and secondary structure prediction. The antigenicity of the selected B-cell peptides was assessed by multiple serological assays using sera from acute P.vivax infected subjects. The synthetic peptides were recognized by 45.5%, 48.7% and 32.2% of infected subjects for peptides I, II and III respectively. Moreover, when synthetized together (tripeptide), the reactivity increases up to 62%, which is comparable to the reactivity found against the whole protein PvAMA-1 (57%). Furthermore, IgG reactivity against the tripeptide after depletion was reduced by 42%, indicating that these epitopes may be responsible for a considerable part of the protein immunogenicity. These results represent an excellent perspective regarding future chimeric vaccine constructions that may come to contemplate several targets with the potential to generate the robust and protective immune response that a vivax malaria vaccine needs to succeed.
- Published
- 2021
40. An engineered vaccine of the Plasmodium vivax Duffy binding protein enhances induction of broadly neutralizing antibodies
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Samantha J. Barnes, John H. Adams, Francis B. Ntumngia, Flora S. Kano, Richard Thomson-Luque, Miriam T. George, Christopher L. King, Darya Urusova, Dhelio Batista Pereira, Camilla V. Pires, Niraj H. Tolia, Luzia H. Carvalho, and Jéssica R. S. Alves
- Subjects
0301 basic medicine ,Immunogen ,Erythrocytes ,030231 tropical medicine ,Plasmodium vivax ,Protozoan Proteins ,Antibodies, Protozoan ,lcsh:Medicine ,Antigens, Protozoan ,Enzyme-Linked Immunosorbent Assay ,Receptors, Cell Surface ,Protein Engineering ,Epitope ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Immunity ,Malaria Vaccines ,Animals ,lcsh:Science ,Mice, Inbred BALB C ,Multidisciplinary ,biology ,Chemistry ,Malaria vaccine ,Immunogenicity ,lcsh:R ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,3. Good health ,030104 developmental biology ,Antibody Formation ,biology.protein ,lcsh:Q ,Antibody ,Protein Binding - Abstract
Plasmodium vivax invasion into human reticulocytes is a complex process. The Duffy binding protein (DBP) dimerization with its cognate receptor is vital for junction formation in the invasion process. Due to its functional importance, DBP is considered a prime vaccine candidate, but variation in B-cell epitopes at the dimer interface of DBP leads to induction of strain-limited immunity. We believe that the polymorphic residues tend to divert immune responses away from functionally conserved epitopes important for receptor binding or DBP dimerization. As a proof of concept, we engineered the vaccine DEKnull to ablate the dominant Bc epitope to partially overcome strain-specific immune antibody responses. Additional surface engineering on the next generation immunogen, DEKnull-2, provides an immunogenicity breakthrough to conserved protective epitopes. DEKnull-2 elicits a stronger broadly neutralizing response and reactivity with long-term persistent antibody responses of acquired natural immunity. By using novel engineered DBP immunogens, we validate that the prime targets of protective immunity are conformational epitopes at the dimer interface. These successful results indicate a potential approach that can be used generally to improve efficacy of other malaria vaccine candidates.
- Published
- 2017
41. Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine
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André Daher, Diego Medeiros Dias da Silva, Dhelio Batista Pereira, Júlio Castro Alves, Márcia A. A. Alexandre, Taís Nóbrega de Sousa, Ana Carolina Rios Silvino, Cristiana T. Nascimento, Laís Bastos da Fonseca, Marcus V. G. Lacerda, Ghait Aljayyoussi, Douglas Pereira Pinto, David G. Lalloo, Cristiana Ferreira Alves de Brito, Danielle Fonseca Rodrigues, and Feiko O. ter Kuile
- Subjects
Male ,0301 basic medicine ,Primaquine ,Plasmodium vivax ,Gastroenterology ,0302 clinical medicine ,Chloroquine ,qv_256 ,Artemether ,biology ,Mefloquine ,Middle Aged ,Artemisinins ,Clinical trial ,Drug Combinations ,Infectious Diseases ,Female ,Brazil ,medicine.drug ,Adult ,medicine.medical_specialty ,lcsh:Arctic medicine. Tropical medicine ,Combination therapy ,lcsh:RC955-962 ,030231 tropical medicine ,030106 microbiology ,qv_38 ,lcsh:Infectious and parasitic diseases ,Antimalarials ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,lcsh:RC109-216 ,Pharmacokinetics ,Aged ,Lumefantrine ,qw_4 ,business.industry ,Research ,biology.organism_classification ,medicine.disease ,ACT ,Artemisinin-based combination therapy ,wc_750 ,Malaria ,Pharmacodynamics ,Anti-malarial treatment ,Parasitology ,business - Abstract
Background Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assurance about the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil. Trial registration RBR-79s56s (http://www.ensaiosclinicos.gov.br/rg/RBR-79s56s/)
- Published
- 2019
42. Ribosomal and non-ribosomal PCR targets for the detection of low-density and mixed malaria infections
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Dhelio Batista Pereira, Cristiana Ferreira Alves de Brito, Taís Nóbrega de Sousa, Daniela Rocha Robortella, L. H. Carvalho, Flora S. Kano, Lara Cotta Amaral, Jean Ezequiel Limongi, Cor Jesus Fernandes Fontes, and Luiz F. F. Guimarães
- Subjects
Male ,Plasmodium vivax ,law.invention ,0302 clinical medicine ,Limit of Detection ,law ,030212 general & internal medicine ,Malaria, Falciparum ,Asymptomatic Infections ,Polymerase chain reaction ,Subclinical infection ,biology ,Coinfection ,Middle Aged ,PCR ,Infectious Diseases ,Molecular Diagnostic Techniques ,Female ,Molecular diagnosis ,medicine.symptom ,Brazil ,Adult ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Plasmodium falciparum ,030231 tropical medicine ,Real-Time Polymerase Chain Reaction ,Asymptomatic ,lcsh:Infectious and parasitic diseases ,Young Adult ,03 medical and health sciences ,parasitic diseases ,Malaria, Vivax ,RNA, Ribosomal, 18S ,medicine ,Humans ,lcsh:RC109-216 ,Research ,Submicroscopic ,Ribosomal RNA ,medicine.disease ,biology.organism_classification ,Virology ,Malaria ,Parasitology ,Mixed-malaria infections - Abstract
Background The unexpected high proportion of submicroscopic malaria infections in areas with low transmission intensity challenges the control and elimination of malaria in the Americas. The current PCR-based assays present limitations as most protocols still rely on amplification of few-copies target gene. Here, the hypothesis was that amplification of different plasmodial targets—ribosomal (18S rRNA) and non-ribosomal multi-copy sequences (Pvr47 for Plasmodium vivax and Pfr364 for Plasmodium falciparum)—could increase the chances of detecting submicroscopic malaria infection. Methods A non-ribosomal real-time PCR assay targeting Pvr47/Pfr364 (NR-qPCR) was established and compared with three additional PCR protocols, two of them based on 18S rRNA gene amplification (Nested-PCR and R-qPCR) and one based on Pvr47/Pfr364 targets (NR-cPCR). The limit of detection of each PCR protocol, at single and artificial mixed P. vivax/P. falciparum infections, was determined by end-point titration curves. Field samples from clinical (n = 110) and subclinical (n = 324) malaria infections were used to evaluate the impact of using multiple molecular targets to detect malaria infections. Results The results demonstrated that an association of ribosomal and non-ribosomal targets did not increase sensitivity to detect submicroscopic malaria infections. Despite of that, artificial mixed-malaria infections demonstrated that the NR-qPCR was the most sensitive protocol to detect low-levels of P. vivax/P. falciparum co-infections. Field studies confirmed that submicroscopic malaria represented a large proportion (up to 77%) of infections among asymptomatic Amazonian residents, with a high proportion of infections (~ 20%) identified only by the NR-qPCR. Conclusions This study presents a new species-specific non-ribosomal PCR assay with potential to identify low-density P. vivax and P. falciparum infections. As the majority of subclinical infections was caused by P. vivax, the commonest form of malaria in the Amazon area, future studies should investigate the potential of Pvr47/Pfr364 to detect mixed-malaria infections in the field. Electronic supplementary material The online version of this article (10.1186/s12936-019-2781-3) contains supplementary material, which is available to authorized users.
- Published
- 2019
43. Author Correction: Caspase-8 mediates inflammation and disease in rodent malaria
- Author
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Marco Antonio Ataide, Caroline Junqueira, Patricia A. Assis, Ricardo T. Gazzinelli, Natalia M. de Araujo, Katherine A. Fitzgerald, Egil Lien, Dario S. Zamboni, Douglas T. Golenbock, Larissa M. N. Pereira, Dhelio Batista Pereira, and Danielle Fernandes Durso
- Subjects
Lipopolysaccharides ,Rodent ,Science ,Interleukin-1beta ,Malaria, Cerebral ,General Physics and Astronomy ,Inflammation ,Disease ,Caspase 8 ,General Biochemistry, Genetics and Molecular Biology ,Monocytes ,Interferon-gamma ,biology.animal ,medicine ,Animals ,Humans ,Author Correction ,lcsh:Science ,Multidisciplinary ,biology ,business.industry ,Caspase 1 ,Toll-Like Receptors ,Brain ,General Chemistry ,Dendritic Cells ,medicine.disease ,Malaria ,Extracellular Matrix ,Enzyme Activation ,Mice, Inbred C57BL ,Gene Expression Regulation ,Plasmodium chabaudi ,Immunology ,Infectious diseases ,lcsh:Q ,medicine.symptom ,business ,Spleen ,Parasite host response - Abstract
Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1β and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.
- Published
- 2020
44. Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria
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Lis Ribeiro do Valle Antonelli, Gustavo B. Menezes, Pedro Marques, Ricardo T. Gazzinelli, Douglas T. Golenbock, Dhelio Batista Pereira, Caroline Junqueira, Bruno Coelho Rocha, and Fabiana M. S. Leoratti
- Subjects
Chemokine ,Population ,INNATE ,IMMUNITY ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,FALCIPARUM MALARIA ,STAGE ,Interferon ,parasitic diseases ,medicine ,PARASITE ,education ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,Reactive oxygen species ,education.field_of_study ,Science & Technology ,EXPERIMENTAL CEREBRAL MALARIA ,biology ,PLASMODIUM-VIVAX MALARIA ,Cell Biology ,MICE ,lcsh:Biology (General) ,chemistry ,Myeloperoxidase ,CELLS ,Immunology ,biology.protein ,LIVER-INJURY ,Signal transduction ,Life Sciences & Biomedicine ,Interferon type I ,medicine.drug - Abstract
Neutrophils are the most abundant leukocyte population in the bloodstream, the primary compartment of Plasmodium sp. infection. However, the role of these polymorphonuclear cells in mediating either the resistance or the pathogenesis of malaria is poorly understood. We report that circulating neutrophils from malaria patients are highly activated, as indicated by a strong type I interferon transcriptional signature, increased expression of surface activation markers, enhanced release of reactive oxygen species and myeloperoxidase, and a high frequency of low-density granulocytes. The activation of neutrophils was associated with increased levels of serum alanine and aspartate aminotransferases, indicating liver damage. In a rodent malaria model, we observed intense recruitment of neutrophils to liver sinusoids. Neutrophil migration and IL-1β and chemokine expression as well as liver damage were all dependent on type I interferon signaling. The data suggest that type I interferon signaling has a central role in neutrophil activation and malaria pathogenesis. ispartof: CELL REPORTS vol:13 issue:12 pages:2829-2841 ispartof: location:United States status: published
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- 2015
45. Phylogenetic Characterization of Arboviruses in Patients Suffering from Acute Fever in Rondônia, Brazil
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Luan Felipo Botelho-Souza, Juan Miguel Vilalobos Salcedo, Deusilene Souza Vieira, Alcione de Oliveira dos Santos, Jackson Alves da Silva Queiroz, Felipe Souza Nogueira-Lima, Miriam Ribas Zambenedetti, Marco Aurélio Krieger, Ivo Alberto Borghetti, Fabricio K. Marchini, Rita de Cássia Pontello Rampazzo, and Dhelio Batista Pereira
- Subjects
Male ,0301 basic medicine ,Serotype ,viruses ,lcsh:QR1-502 ,medicine.disease_cause ,lcsh:Microbiology ,Disease Outbreaks ,Dengue fever ,Dengue ,0302 clinical medicine ,Genotype ,Chikungunya ,Phylogeny ,Sanger sequencing ,education.field_of_study ,Coinfection ,virus diseases ,Viral Load ,Infectious Diseases ,arboviruses ,Acute Disease ,symbols ,RNA, Viral ,Female ,Viral load ,Brazil ,Fever ,030231 tropical medicine ,Population ,Arbovirus Infections ,Biology ,Serogroup ,Article ,Evolution, Molecular ,03 medical and health sciences ,symbols.namesake ,Virology ,medicine ,Humans ,education ,Genotyping ,Dengue Virus ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,030104 developmental biology ,genotyping ,phylogenetic - Abstract
The purpose of the study was to classify, through phylogenetic analyses, the main arboviruses that have been isolated in the metropolitan region of Porto Velho, Rondô, nia, Brazil. Serum samples from patients with symptoms suggesting arboviruses were collected and tested by One Step RT-qPCR for Zika, Dengue (serotypes 1&ndash, 4), Chikungunya, Mayaro and Oropouche viruses. Positive samples were amplified by conventional PCR and sequenced utilizing the Sanger method. The obtained sequences were aligned, and an evolutionary analysis was carried out using Bayesian inference. A total of 308 samples were tested. Of this total, 20 had a detectable viral load for Dengue, being detected DENV1 (18/20), co-infection DENV1 and DENV2 (1/20) and DENV4 (1/20). For Dengue serotype 3 and for the CHIKV, ZIKV, MAYV and OROV viruses, no individuals with a detectable viral load were found. A total of 9 of these samples were magnified by conventional PCR for sequencing. Of these, 6 were successfully sequenced and, according to the evolutionary profile, 5 corresponded to serotype DENV-1 genotype V, and 1 to serotype DENV-4 genotype II. In the study, we demonstrate co-circulation of the DENV-1 genotype V and the DENV-4 genotype II. Co-circulation of several DENV serotypes in the same city poses a risk to the population and is correlated with the increase of the most severe forms of the disease. Similarly, co-circulation of genetically distinct DENV and the occurrence of simultaneous infections can affect recombination events and lead to the emergence of more virulent isolates.
- Published
- 2020
46. Induction of Inhibitory Receptors on T Cells DuringPlasmodium vivaxMalaria Impairs Cytokine Production
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Maria Marta Figueiredo, Daniel L. Barber, Lis Ribeiro do Valle Antonelli, Pedro A C Costa, Ricardo T. Gazzinelli, Mauro Shugiro Tada, Fabiana M. S. Leoratti, Caroline Junqueira, Irene S. Soares, and Dhelio Batista Pereira
- Subjects
Adult ,Male ,T-Lymphocytes ,Plasmodium vivax ,Receptors, Antigen, T-Cell ,RECEPTORES ,Immune tolerance ,Young Adult ,Major Articles and Brief Reports ,Interleukin 21 ,Immune system ,Antigen ,parasitic diseases ,Immune Tolerance ,Malaria, Vivax ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,biology ,Middle Aged ,biology.organism_classification ,Cell biology ,Infectious Diseases ,Host-Pathogen Interactions ,Immunology ,Cytokines ,Female ,CD8 - Abstract
The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4(+) and CD8(+) T cells. Higher frequencies of CD4(+) express more than 1 regulatory molecule compared to CD8(+) T cells. Moreover, lower proportions of CD4(+) T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin-3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function.
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- 2015
47. Adenosine pathway regulates inflammation during Plasmodium vivax infection
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Suelen Queiroz Diniz, Maria Marta Figueiredo, Pedro Augusto Carvalho Costa, Olindo Assis Martins-Filho, Andrea Teixeira-Carvalho, Dhélio Batista Pereira, Mauro Shugiro Tada, Luis Carlos Crocco Afonso, Markus Kohlhoff, Carlos Leomar Zani, Ricardo Tostes Gazzinelli, Fabiano Oliveira, and Lis Ribeiro Antonelli
- Subjects
malaria ,Plasmodium vivax ,ectonucleotidases ,adenosine ,regulation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundPlasmodium spp. infection triggers the production of inflammatory cytokines that are essential for parasite control, and conversely responsible for symptoms of malaria. Monocytes play a role in host defense against Plasmodium vivax infection and represent the main source of inflammatory cytokines and reactive oxygen species. The anti-inflammatory cytokine IL-10 is a key regulator preventing exacerbated inflammatory responses. Studies suggested that different clinical presentations of malaria are strongly associated with an imbalance in the production of inflammatory and anti-inflammatory cytokines.MethodsA convenience sampling of peripheral blood mononuclear cells from Plasmodium vivax-infected patients and healthy donors were tested for the characterization of cytokine and adenosine production and the expression of ectonucleotidases and purinergic receptors.ResultsHere we show that despite a strong inflammatory response, monocytes also bear a modulatory role during malaria. High levels of IL-10 are produced during P. vivax infection and its production can be triggered in monocytes by P. vivax-infected reticulocytes. Monocytes express high levels of ectonucleotidases, indicating their important role in extracellular ATP modulation and consequently in adenosine production. Plasmatic levels of adenosine are not altered in patients experiencing acute malaria; however, their monocyte subsets displayed an increased expression of P1 purinergic receptors. In addition, adenosine decreases Tumor Necrosis Factor production by monocytes, which was partially abolished with the blockage of the A2a receptor.ConclusionMonocytes have a dual role, attempting to control both the P. vivax infection and the inflammatory response. Purinergic receptor modulators emerge as an untapped approach to ameliorate clinical malaria.
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- 2023
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48. On the cytokine/chemokine network during Plasmodium vivax malaria: new insights to understand the disease
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Ricardo Toshio Fujiwara, Dhelio Batista Pereira, Daniella Castanheira Bartholomeu, Mariana Santos Cardoso, Fernanda S. H. Souza, Graziela Maria Zanini, Tiago Antônio de Oliveira Mendes, Lilian Lacerda Bueno, Natália Satchiko Hojo-Souza, and Mauro Shugiro Tada
- Subjects
Adult ,Male ,0301 basic medicine ,Chemokine ,media_common.quotation_subject ,medicine.medical_treatment ,030231 tropical medicine ,Plasmodium vivax ,CCL2 ,CCL5 ,Plasma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Malaria, Vivax ,medicine ,Humans ,CXCL10 ,Aged ,media_common ,Aged, 80 and over ,Immunoassay ,biology ,Research ,Convalescence ,Middle Aged ,biology.organism_classification ,medicine.disease ,Malaria ,030104 developmental biology ,Infectious Diseases ,Cytokine ,Immunology ,biology.protein ,Cytokines ,Female ,Parasitology ,Chemokines - Abstract
Background The clinical outcome of malaria depends on the delicate balance between pro-inflammatory and immunomodulatory cytokine responses triggered during infection. Despite the numerous reports on characterization of plasma levels of cytokines/chemokines, there is no consensus on the profile of these mediators during blood stage malaria. The identification of acute phase biomarkers might contribute to a better understanding of the disease, allowing the use of more effective therapeutic approaches to prevent the progression towards severe disease. In the present study, the plasma levels of cytokines and chemokines and their association with parasitaemia and number of previous malaria episodes were evaluated in Plasmodium vivax-infected patients during acute and convalescence phase, as well as in healthy donors. Methods Samples of plasma were obtained from peripheral blood samples from four different groups: P. vivax-infected, P. vivax-treated, endemic control and malaria-naïve control. The cytokine (IL-6, IL-10, IL-17, IL-27, TGF-β, IFN-γ and TNF) and chemokine (MCP-1/CCL2, IP-10/CXCL10 and RANTES/CCL5) plasma levels were measured by CBA or ELISA. The network analysis was performed using Spearman correlation coefficient. Results Plasmodium vivax infection induced a pro-inflammatory response driven by IL-6 and IL-17 associated with an immunomodulatory profile mediated by IL-10 and TGF-β. In addition, a reduction was observed of IFN-γ plasma levels in P. vivax group. A lower level of IL-27 was observed in endemic control group in comparison to malaria-naïve control group. No significant results were found for IL-12p40 and TNF. It was also observed that P. vivax infection promoted higher levels of MCP-1/CCL2 and IP-10/CXCL10 and lower levels of RANTES/CCL5. The plasma level of IL-10 was elevated in patients with high parasitaemia and with more than five previous malaria episodes. Furthermore, association profile between cytokine and chemokine levels were observed by correlation network analysis indicating signature patterns associated with different parasitaemia levels. Conclusions The P. vivax infection triggers a balanced immune response mediated by IL-6 and MCP-1/CCL2, which is modulated by IL-10. In addition, the results indicated that IL-10 plasma levels are influenced by parasitaemia and number of previous malaria episodes.
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- 2017
49. T follicular helper cells regulate the activation of B lymphocytes and antibody production during Plasmodium vivax infection
- Author
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Dragana Jankovic, Suelen Queiroz Diniz, Flora S. Kano, Mauro Sugiro Tada, Ricardo T. Gazzinelli, Maria Marta Figueiredo, Olindo Assis Martins-Filho, Priscilla M. Henriques, Pedro A C Costa, Dhelio Batista Pereira, Irene S. Soares, and Lis Ribeiro do Valle Antonelli
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0301 basic medicine ,Male ,Plasmodium ,B Cells ,Physiology ,Plasmodium vivax ,Antibodies, Protozoan ,Lymphocyte Activation ,Biochemistry ,Mice ,White Blood Cells ,0302 clinical medicine ,Cognition ,Learning and Memory ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Biology (General) ,B-Lymphocytes ,Immune System Proteins ,biology ,T Cells ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,3. Good health ,medicine.anatomical_structure ,Female ,Antibody ,Cellular Types ,Research Article ,Adult ,Adolescent ,QH301-705.5 ,CD3 ,Immune Cells ,Naive B cell ,Immunology ,Plasma Cells ,Microbiology ,Antibodies ,03 medical and health sciences ,Young Adult ,Memory ,Virology ,Parasite Groups ,parasitic diseases ,Genetics ,medicine ,Malaria, Vivax ,Parasitic Diseases ,Animals ,Humans ,PLASMODIUM ,Antibody-Producing Cells ,Molecular Biology ,B cell ,CD40 ,Blood Cells ,Germinal center ,Biology and Life Sciences ,Proteins ,Cell Biology ,RC581-607 ,biology.organism_classification ,Tropical Diseases ,Memory B cells ,Malaria ,B-1 cell ,030104 developmental biology ,biology.protein ,Cognitive Science ,Parasitology ,Immunologic diseases. Allergy ,Apicomplexa ,030215 immunology ,Neuroscience - Abstract
Although the importance of humoral immunity to malaria has been established, factors that control antibody production are poorly understood. Follicular helper T cells (Tfh cells) are pivotal for generating high-affinity, long-lived antibody responses. While it has been proposed that expansion of antigen-specific Tfh cells, interleukin (IL) 21 production and robust germinal center formation are associated with protection against malaria in mice, whether Tfh cells are found during Plasmodium vivax (P. vivax) infection and if they play a role during disease remains unknown. Our goal was to define the role of Tfh cells during P. vivax malaria. We demonstrate that P. vivax infection triggers IL-21 production and an increase in Tfh cells (PD-1+ICOS+CXCR5+CD45RO+CD4+CD3+). As expected, FACS-sorted Tfh cells, the primary source of IL-21, induced immunoglobulin production by purified naïve B cells. Furthermore, we found that P. vivax infection alters the B cell compartment and these alterations were dependent on the number of previous infections. First exposure leads to increased proportions of activated and atypical memory B cells and decreased frequencies of classical memory B cells, whereas patients that experienced multiple episodes displayed lower proportions of atypical B cells and higher frequencies of classical memory B cells. Despite the limited sample size, but consistent with the latter finding, the data suggest that patients who had more than five infections harbored more Tfh cells and produce more specific antibodies. P. vivax infection triggers IL-21 production by Tfh that impact B cell responses in humans., Author summary Plasmodium vivax is the most widely spread malaria parasite species and represents a significant impediment to social and economic development in endemic countries. Our goal was to assess the importance of T follicular helper cells in the development of the immune response during malaria. We found that P. vivax infection promotes expansion of circulating Tfh cells that secrete IL-21 to boost immunoglobulin production by B-cells. Accordingly, malaria infection led to marked changes in B cell subpopulations, including expansion of plasma cells and increased production of antigen-specific IgG1 and IgG3. Re-exposure to P. vivax led to amplified Tfh cells cell responses that were concomitantly associated with increased frequencies of classical memory B cells. Thus, Tfh cells that are induced during P. vivax infection could impact the efficiency of humoral immune responses that underlie protective immunity.
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- 2017
50. Cross-reactive anti-PfCLAG9 antibodies in the sera of asymptomatic parasite carriers of Plasmodium vivax
- Author
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Fernando B. Zanchi, Mauro Shugiro Tada, Tony Hiroschi Katsuragawa, Eduardo Rezende Honda, Joana D'Arc Neves Costa, Dhelio Batista Pereira, Luiz Hildebrando Pereira-da-Silva, Ricardo de Godoi Mattos Ferreira, Francisco Lurdevanhe da Silva Rodrigues, and Roger Lafontaine Mesquita Taborda
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Microbiology (medical) ,lcsh:Arctic medicine. Tropical medicine ,Erythrocytes ,lcsh:RC955-962 ,Plasmodium vivax ,Plasmodium falciparum ,lcsh:QR1-502 ,malaria ,Protozoan Proteins ,Antibodies, Protozoan ,Antigens, Protozoan ,Enzyme-Linked Immunosorbent Assay ,Biology ,Cross Reactions ,Plasmodium ,lcsh:Microbiology ,Mice ,Immune system ,Antigen ,Immunity ,parasitic diseases ,Malaria, Vivax ,Animals ,Humans ,Malaria, Falciparum ,cross-reaction ,Amazon ,Mice, Inbred BALB C ,Immunogenicity ,Articles ,biology.organism_classification ,Virology ,immunity ,Immunology ,Carrier State ,biology.protein ,Female ,Antibody ,Cell Adhesion Molecules ,Brazil - Abstract
The PfCLAG9 has been extensively studied because their immunogenicity. Thereby, the gene product is important for therapeutics interventions and a potential vaccine candidate. Antibodies against synthetic peptides corresponding to selected sequences of the Plasmodium falciparum antigen PfCLAG9 were found in sera of falciparum malaria patients from Rondônia, in the Brazilian Amazon. Much higher antibody titres were found in semi-immune and immune asymptomatic parasite carriers than in subjects suffering clinical infections, corroborating original findings in Papua Guinea. However, sera of Plasmodium vivax patients from the same Amazon area, in particular from asymptomatic vivax parasite carriers, reacted strongly with the same peptides. Bioinformatic analyses revealed regions of similarity between P. falciparum Pfclag9 and the P. vivax ortholog Pvclag7. Indirect fluorescent microscopy analysis showed that antibodies against PfCLAG9 peptides elicited in BALB/c mice react with human red blood cells (RBCs) infected with both P. falciparum and P. vivax parasites. The patterns of reactivity on the surface of the parasitised RBCs are very similar. The present observations support previous findings that PfCLAG9 may be a target of protective immune responses and raises the possibility that the cross reactive antibodies to PvCLAG7 in mixed infections play a role in regulate the fate of Plasmodium mixed infections.
- Published
- 2013
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