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1. Risk of transfusion-transmitted malaria: evaluation of commercial ELISA kits for the detection of anti-Plasmodium antibodies in candidate blood donors

Author

Valentina D. Mangano, Francesca Perandin, Natalia Tiberti, Massimo Guerriero, Franca Migliaccio, Marco Prato, Lucia Bargagna, Stefano Tais, Monica Degani, Federica Verra, Zeno Bisoffi, and Fabrizio Bruschi

Subjects
Plasmodium, Transfusion transmitted malaria, ELISA, IFAT, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Transfusion with Plasmodium-infected blood represents a risk for malaria transmission, a rare but severe event. Several non-endemic countries implement a strategy for the screening of candidate blood donors including questionnaire for the identification of at-risk subjects and laboratory testing of blood samples, often serology-based, with temporary deferral from donation for individuals with a positive result. In Italy, the most recent legislation, issued in November 2015, introduced the use of serological tests for the detection of anti-Plasmodium antibodies. Methods In the absence of a gold standard for malaria serology, the aim of this work was to evaluate five commercial ELISA kits, and to determine their accuracy (sensitivity and specificity) in comparison to immuno-fluorescence antibody test (IFAT), and their agreement (concordance of results). Serum samples from malaria patients or from subjects with malaria history (N = 64), malaria naïve patients with other parasitic infections (N = 15), malaria naïve blood donors (N = 8) and malaria exposed candidate blood donors (N = 36) were tested. Results The specificity of all ELISA kits was 100%, while sensitivity ranged between 53 and 64% when compared to IFAT on malaria patients samples. When tested on candidate blood donors’ samples, ELISA kits showed highly variable agreement (42–94%) raising the possibility that the same individual could be included or excluded from donation depending on the test in use by the transfusion centre. Conclusions These preliminary results indicate how the lack of a gold standard for malaria serology must be taken into account in the application and future revision of current legislation. There is need of developing more sensitive serological assays. Moreover, the adoption of a unique serological test at national level is recommended, as well as the development of screening algorithms based on multiple laboratory tests, including molecular assays.

Published
2019
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2. An Unexpected Case of Opisthorchis felineus Infection Revealed during Liver Transplantation

Author

Valentina D Mangano, Daniela Campani, Andrea Cacciato Insilla, Barbara Coco, Maria Angeles Gomez Morales, Maurizia Brunetto, Giuseppe La Rosa, Alessandra Ludovisi, Paolo De Simone, and Fabrizio Bruschi

Subjects
Opistorchis, liver transplant, parasitic infection, Medicine
Abstract

A man with hepatitis B infection was admitted to Pisa University Hospital for hepatological evaluation, which revealed multiple cystic lesions and suggested a cirrhotic evolution. Treatment with Entecavir 0.5 mg/day was started, resulting in rapid viral load suppression and alanine aminotransferase normalization. After 10 years, imaging documented a single nodule of hepatocellular carcinoma (HCC), and a robot-assisted nodule resection was performed. One year later, HCC recurrence prompted orthotopic liver transplantation, during which the patient died because of the sudden rupture of the donor’s organ and rapid multiorgan deterioration before retransplantation. During post-mortem liver examination, adult worms were evidenced within large biliary ducts, suggesting infection with Opisthorchis or Clonorchis spp. flukes. Sequencing of the ITS2 locus, following PCR amplification of DNA extracted from liver tissue, revealed 100% identity with the reference sequence of O. felineus. Infection of the patient with O. felineus was confirmed by the presence of specific IgG detected by ELISA in the patient’s sera. Two major alkaline phosphatase serum levels peaks observed during the first two years of antiviral therapy support the hypothesis that O. felineus infection worsened liver function. This case report highlights the importance of a very careful screening of parasitic infections in solid organ transplantation candidates.

Published
2023
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3. Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Author

Geraldine M Clarke, Kirk Rockett, Katja Kivinen, Christina Hubbart, Anna E Jeffreys, Kate Rowlands, Muminatou Jallow, David J Conway, Kalifa A Bojang, Margaret Pinder, Stanley Usen, Fatoumatta Sisay-Joof, Giorgio Sirugo, Ousmane Toure, Mahamadou A Thera, Salimata Konate, Sibiry Sissoko, Amadou Niangaly, Belco Poudiougou, Valentina D Mangano, Edith C Bougouma, Sodiomon B Sirima, David Modiano, Lucas N Amenga-Etego, Anita Ghansah, Kwadwo A Koram, Michael D Wilson, Anthony Enimil, Jennifer Evans, Olukemi K Amodu, Subulade Olaniyan, Tobias Apinjoh, Regina Mugri, Andre Ndi, Carolyne M Ndila, Sophie Uyoga, Alexander Macharia, Norbert Peshu, Thomas N Williams, Alphaxard Manjurano, Nuno Sepúlveda, Taane G Clark, Eleanor Riley, Chris Drakeley, Hugh Reyburn, Vysaul Nyirongo, David Kachala, Malcolm Molyneux, Sarah J Dunstan, Nguyen Hoan Phu, Nguyen Ngoc Quyen, Cao Quang Thai, Tran Tinh Hien, Laurens Manning, Moses Laman, Peter Siba, Harin Karunajeewa, Steve Allen, Angela Allen, Timothy ME Davis, Pascal Michon, Ivo Mueller, Síle F Molloy, Susana Campino, Angeliki Kerasidou, Victoria J Cornelius, Lee Hart, Shivang S Shah, Gavin Band, Chris CA Spencer, Tsiri Agbenyega, Eric Achidi, Ogobara K Doumbo, Jeremy Farrar, Kevin Marsh, Terrie Taylor, Dominic P Kwiatkowski, and MalariaGEN Consortium

Subjects
G6PD deficiency, genetic association, infectious disease, selection, Medicine, Science, Biology (General), QH301-705.5
Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.

Published
2017
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4. Admixture into and within sub-Saharan Africa

Author

George BJ Busby, Gavin Band, Quang Si Le, Muminatou Jallow, Edith Bougama, Valentina D Mangano, Lucas N Amenga-Etego, Anthony Enimil, Tobias Apinjoh, Carolyne M Ndila, Alphaxard Manjurano, Vysaul Nyirongo, Ogobara Doumba, Kirk A Rockett, Dominic P Kwiatkowski, Chris CA Spencer, and Malaria Genomic Epidemiology Network

Subjects
admixture, chromosome painting, Africa, gene-flow, Medicine, Science, Biology (General), QH301-705.5
Abstract

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.

Published
2016
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5. Picoradiant tiltmeter and direct ground tilt measurements at the Sos Enattos site

Author

Martina De Laurentis, Enrico Calloni, Naurang L. Saini, F. Ricci, Valeria Sipala, Francesco Tafuri, D. Rozza, Valentina D. Mangano, Sergio Caprara, Rosario De Rosa, P. Puppo, G.P. Pepe, Maria Marsella, L. Naticchioni, M. Carpinelli, P. Ruggi, G. Gagliardi, A. Pasqualetti, Marco Grilli, Luigi Rosa, Daniela Stornaiuolo, P. Rapagnani, A. Allocca, Carlo Rovelli, L. Errico, D. D'Urso, M. Perciballi, V. Sequino, Luca Pesenti, Saverio Avino, Allocca, A., Avino, S., Calloni, E., Caprara, S., Carpinelli, M., D'Urso, D., De Laurentis, M., De Rosa, R., Errico, L., Gagliardi, G., Grilli, M., Mangano, V., Marsella, M., Naticchioni, L., Pasqualetti, A., Pepe, G., Perciballi, M., Pesenti, L., Puppo, P., Rapagnani, P., Ricci, F., Rosa, L., Rovelli, C., Rozza, D., Ruggi, P., Saini, N. L., Sequino, V., Sipala, V., Stornaiuolo, D., Tafuri, F., Allocca, A, Avino, S, Calloni, E, Caprara, S, Carpinelli, M, D'Urso, D, De Laurentis, M, De Rosa, R, Errico, L, Gagliardi, G, Grilli, M, Mangano, V, Marsella, M, Naticchioni, L, Pasqualetti, A, Pepe, G, Perciballi, M, Pesenti, L, Puppo, P, Rapagnani, P, Ricci, F, Rosa, L, Rovelli, C, Rozza, D, Ruggi, P, Saini, N, Sequino, V, Sipala, V, Stornaiuolo, D, Tafuri, F, Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), CPT - E4 Gravité quantique, and Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physics, Einstein Telescope, Gravitational wave, General Physics and Astronomy, Tiltmeter, Seismic noise, Computational physics, Interferometry, Tilt (optics), picoradiant tiltmeter, direct ground tilt measurements, sos enattos site, archimedes, [PHYS.GRQC]Physics [physics]/General Relativity and Quantum Cosmology [gr-qc], Sensitivity (control systems), Noise, ComputingMilieux_MISCELLANEOUS, Noise (radio)
Abstract

We report the tilt sensitivity reached by the ARCHIMEDES tiltmeter in the 2–20 Hz frequency region, where seismic noise is expected to give an important limitation to the sensitivity in the next future Gravitational Waves detection, particularly through Newtonian noise. The tilt noise level $$\tilde{\theta }(f)$$ θ ~ ( f ) is about $$10^{-12} \mathrm{rad}/\sqrt{\mathrm{Hz}}$$ 10 - 12 rad / Hz in most of the band, reaching the minimum of $$\tilde{\theta } = 7\cdot 10^{-13} \mathrm{rad}/\sqrt{\mathrm{Hz}}$$ θ ~ = 7 · 10 - 13 rad / Hz around 9 Hz. The tiltmeter is a beam balance with a 0.5 m suspended arm and interferometric optical readout, working in closed loop. The results have been obtained by a direct measurement of the ground tilt at the Sos Enattos site (Sardinia, Italy). This sensitivity is a requirement to use the tiltmeter as part of an effective Newtonian noise reduction system for present Gravitational Waves detectors, and also confirms that Sos Enattos is among the quietest sites in the world, suitable to host the third-generation Gravitational Waves detector Einstein Telescope.

Published
2021

6. Antibody response to Schistosoma haematobium and other helminth species in malaria-exposed populations from Burkina Faso

Author

David Modiano, Mireille Ouedraogo, Youssouf Kaboré, Claretta Bianchi, Fabrizio Bruschi, Valentina D. Mangano, Patrick H. Corran, Nilupa Silva, Issa Nebie, and Sodiomon B. Sirima

Subjects
Male, 0301 basic medicine, medicine.disease_cause, fulani, immunity, lymphatic filariasis, malaria, schistosomiasis, soil-transmitted helminths, sub-saharan africa, 0302 clinical medicine, Malaria, Falciparum, Child, Lymphatic filariasis, Schistosoma haematobium, education.field_of_study, biology, Middle Aged, 030108 mycology & parasitology, Infectious Diseases, Wuchereria bancrofti, Child, Preschool, Female, Falciparum, Adult, Adolescent, Veterinary (miscellaneous), 030231 tropical medicine, Population, Antibodies, Helminth, Fulani, Immunity, Malaria, Schistosomiasis, Soil-transmitted helminths, Sub-Saharan Africa, Animals, Burkina Faso, Humans, Immunoglobulin G, Infant, Infant, Newborn, Young Adult, Antibodies, Strongyloides stercoralis, 03 medical and health sciences, parasitic diseases, Helminth, medicine, Helminths, Preschool, education, Plasmodium falciparum, Newborn, medicine.disease, biology.organism_classification, Insect Science, Immunology, Parasitology
Abstract

Infection with helminths in sub-Saharan Africa could modulate the immune response towards Plasmodium falciparum as well as susceptibility to malaria infection and disease. The aim of this study is to assess the antibody responses to helminths species in malaria-exposed populations from Burkina Faso. Plasma samples were collected in rural villages inhabited by Fulani, Mossi and Rimaibe communities, and IgG against parasitic helminths were measured by ELISA. The prevalence of IgG against antigens of Strongyloides stercoralis, Wuchereria bancrofti and Schistosoma haematobium (Soluble Egg Antigen, SEA) was 5%, 16% and 63% respectively, in line with estimates of infection prevalence in the region for the three parasites. Anti-SEA IgG prevalence was highest at 10–20 years of age, higher in males than females, and did not show differences between ethnic groups. However, the Fulani showed lower levels of anti-SEA IgG suggesting that lighter S. haematobium infections may occur in the ethnic group known for a marked lower susceptibility to P. falciparum. The present data support the use of serological methods for integrated surveillance of neglected tropical diseases such as soil-transmitted helminths, lymphatic filariasis and bilharzia. Furthermore, as helminth infections might promote downregulation of immune responses against intracellular pathogens, the observation of lower anti-SEA IgG levels in the malaria resistant Fulani population warrants further investigation into the immunological cross-talk between S. haematobium and P. falciparum in this geographical region.

Published
2020

7. Progress in a Vacuum Weight Search Experiment

Author

Saverio Avino, M. Perciballi, Arturo Tagliacozzo, Giovanni Piero Pepe, L. Errico, Carlo Rovelli, Luigi Rosa, Gianluca Gagliardi, Naurang L. Saini, Valentina D. Mangano, Maria Marsella, L. Naticchioni, Enrico Calloni, Tristano Di Girolamo, F. Ricci, P. Puppo, Rosario De Rosa, Martina De Laurentis, Sergio Caprara, Daniela Stornaiuolo, P. Rapagnani, P. Ruggi, Francesco Tafuri, Gabriel Pillant, Marco Grilli, Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Université de Toulon (UTLN), Avino, Saverio, Calloni, Enrico, Caprara, Sergio, De Laurentis, Martina, De Rosa, Rosario, Di Girolamo, Tristano, Errico, Luciano, Gagliardi, Gianluca, Grilli, Marco, Mangano, Valentina, Marsella, Maria Antonietta, Naticchioni, Luca, Pepe, Giovanni Piero, Perciballi, Maurizio, Pillant, Gabriel, Puppo, Paola, Rapagnani, Piero, Ricci, Fulvio, Rosa, Luigi, Rovelli, Carlo, Ruggi, Paolo, Saini, Naurang L., Stornaiuolo, Daniela, Tafuri, Francesco, and Tagliacozzo, Arturo

Subjects
noise, 01 natural sciences, Signal, Noise (electronics), thermal, energy: transition, vacuum state: energy, vacuum energy, Vacuum energy, fluctuation: quantum, 0103 physical sciences, Thermal, site, [PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex], Sensitivity (control systems), 010306 general physics, Quantum fluctuation, Physics, energy: Casimir, 010308 nuclear & particles physics, superconductivity, quantum fluctuations, temperature, sensitivity, quantum fluctuations, gravity, vacuum energy, Casimir energy, lcsh:QC1-999, Computational physics, gravity, Casimir energy, Casimir effect, cryogenics: design, fluctuation: vacuum, gravitation, proposed experiment, lcsh:Physics, Energy (signal processing)
Abstract

International audience; We present the status of the art of the Archimedes experiment, devoted to measuring the debated interaction of quantum vacuum fluctuations and gravity. The method is essentially the weighing of the transition energy of a layered superconductor where the contribution of vacuum energy to the transition energy is expected to be relevant. The transition is obtained by modulating the temperature of the superconducting sample at a frequency of about 10 mHz and the expected change of weight is measured with a suitably designed high sensitivity cryogenic beam balance. In this paper, we present an overview of the experiment, discussing the expected signal to be measured, and presenting in particular the result of a prototype balance operated in our present laboratory. In the frequency range of the measurement, the sensitivity is affected mainly by seismic, thermal, sensor, and control noise. We discuss these points showing in particular the design of the cryogenic apparatus, the final balance, and the quiet seismic site that will host the final measurement.

Published
2020

8. New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania

Author

Kate Rowlands, Timothy M. E. Davis, Salimata Konate, Umberto D'Alessandro, Angeliki Kerasidou, Sodiomon B. Sirima, David J. Conway, Fatoumatta Sisay-Joof, S Ademola, Mahamadou A. Thera, Momodou W. Jallow, Edith C. Bougouma, Alexander J. Mentzer, Alphaxard Manjurano, Chris Drakeley, Carolyne M. Ndila, Giorgio Sirugo, Eleanor Drury, Nguyen Hoan Phu, Moses Laman, Anthony Enimil, Pascal Michon, N T Ngoc Quyen, Terrie E. Taylor, Jennifer Evans, Ogobara K. Doumbo, Anita Ghansah, Malcolm E. Molyneux, Alexander T. Dilthey, Sibiry Sissoko, Olukemi K. Amodu, Kalifa Bojang, Yik Ying Teo, Ousmane Touré, Eleanor M. Riley, Dominic P. Kwiatkowski, Angela Allen, Laurens Manning, D Ansong, Peter Siba, Stephen Allen, Thomas N. Williams, Christina Hubbart, Tobias O. Apinjoh, Cao Quang Thai, Hugh Reyburn, Q S Le, Melanie Bahlo, Geraldine M. Clarke, Spencer Cca., Ivo Mueller, Anna E. Jeffreys, Gil McVean, Valentina D. Mangano, Jj J. Farrar, Victoria Cornelius, Busby Gbj., Kevin Marsh, Jim Stalker, David Modiano, Tran Tinh Hien, Michael T. Wilson, Tsiri Agbenyega, A Hodgson, Sarah J. Dunstan, Harin Karunajeewa, L. Amenga-Etego, Ellen M. Leffler, Katja Kivinen, Eric A. Achidi, Kirk A. Rockett, Kwadwo A. Koram, and J Shelton

Subjects
Genetics, Host resistance, biology, Plasmodium falciparum, Disease, Heritability, Hla association, biology.organism_classification, medicine.disease, Genome, Cerebral Malaria, parasitic diseases, medicine, Malaria
Abstract

We conducted a genome-wide association study of host resistance to severePlasmodium falciparummalaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association inATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h2~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.

Published
2019

9. Imported human Schistosoma japonicum: A report on two cases in Filipino migrants present in Italy and a systematic review of literature

Author

Fabrizio Bruschi, Federico Gobbi, Lorenzo Zammarchi, Valentina D. Mangano, Iacopo Vellere, Daniela Campani, Paolo De Simone, Giandomenico Luigi Biancofiore, Alessandro Bartoloni, Maria Cristina Cagno, and Andrea Ragusa

Subjects
Adult, Pediatrics, medicine.medical_specialty, medicine.medical_treatment, Philippines, 030231 tropical medicine, Schistosomiasis, Liver transplantation, Asymptomatic, Schistosoma japonicum, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, medicine, Animals, Humans, 030212 general & internal medicine, Transients and Migrants, biology, business.industry, Public Health, Environmental and Occupational Health, Explorative laparotomy, medicine.disease, biology.organism_classification, Transplantation, Praziquantel, Infectious Diseases, Italy, Acute abdomen, Schistosomiasis japonica, medicine.symptom, business, medicine.drug
Abstract

Background Schistosoma japonicum is endemic in the Philippines, China, and Indonesia, and is the third-most common schistosoma species. The infection can be asymptomatic for years but, if left untreated, can lead to irreversible complications. Method We report the results of a systematic review of the literature on imported S. japonicum infection and describe two previously unpublished cases diagnosed in Filipino migrants in Italy. Results Twenty-five imported cases of S. japonicum schistosomiasis were retrieved. All patients but one were migrants. Most subjects acquired the infection in Philippines (n = 18, 72%). Median age at diagnosis was 46 years. Median period of residence in non-endemic countries before diagnosis was 14.5 years. Cases of prevalent hepatosplenic involvement were 10 (40%), those with prevalent intestinal involvement were 10 (40%), whereas five (20%) had overlapping manifestations. Ten patients suffered from cirrhosis; two underwent liver transplantation. Three patients presented with acute abdomen due to intestinal complications, leading to explorative laparotomy. In all cases, but one, the diagnosis was based on a histological examination of biopsy specimen, revealing S. japonicum ova. Seventeen patients were treated with praziquantel, and in three of them, possible treatment failures occurred. Conclusions S. japonicum infection is uncommonly reported in non-endemic areas, but is probably underestimated because of a low threshold awareness of clinicians and unavailability of specific diagnostic tools. Viable S. japonicum adults may persist for decades, indicating that migrants or travellers previously exposed in areas with high-risk areas can harbour viable worms and deserve treatment.

Published
2019

10. Seroreactivity of Populations Living in Endemic Area of Burkina Faso to Plasmodium falciparum Alpha-Helical Coiled Coil Proteins Motifs by Protein Microarray

Author

Valentina D. Mangano, Blami Kote, Oumarou Ouédraogo, Alfred B. Tiono, Issa Nebie, David Modiano, Edith C. Bougouma, Giampietro Corradin, Roberta Spaccapelo, Yves Traoré, Youssouf Kaboré, Luisa Nunziangeli, Amidou Diarra, and Sodiomon B. Sirima

Subjects
0301 basic medicine, Plasmodium falciparum, Protein microarray, Naturally acquired immunity, Malaria vaccine, biology, medicine.disease, biology.organism_classification, Acquired immune system, Virology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Antigen, Immunity, Genotype, medicine, 030217 neurology & neurosurgery, Malaria
Abstract

The naturally acquired immunity is one of the models of immunity that is exploited for malaria antigens discovery. We have used multiplex protein microarrays of 92 P. falciparum alpha-helical coiled coil protein motifs to screen plasma samples obtained from 1113 children and adults belonging to three sympatric ethnic groups from malaria endemic area of Burkina Faso. We have investigated the influence of some factors such as age, ethnicity, hemoglobin genotype and sex on the antigens reactivity and the IgG antibody level. We also investigated specifically, the influence of the factors mentioned above on the 36 antigens with the highest antibody prevalence and intensity. As expected, the findings of the study confirmed the positive correlation between age, antigens reactivity and IgG antibody level. Except for three antigens (MSP2_3D7, MR260, and As182.20), the IgG level was higher in adults compared to children. The Fulani ethnic group recognized more antigens with the highest IgG values compared to the sympatric groups of Mossi and Rimaibe, except for six antigens (LR166, LR146, AS182.15, MR214, MR236A, and MSP3). In General, the hemoglobin type and sex did not have any influence on the IgG antibody reactivity and intensity. Except for four antigens (MR232, MR261A, MSP2_3D7, and NANP) 10), there was statistically no IgG intensity difference between people with normal hemoglobin genotype (AA) and the non-(AA) volunteers. Our study has demonstrated that protein microarrays of alpha-helical coiled-coil proteins motifs are suitable to screen the naturally acquired immunity. The findings of the study should be considered in any strategy for new antigen related to alpha-helical coiled coil protein segments discovery for a potential vaccine clinical development.

Published
2019

11. Risk of transfusion-transmitted malaria: evaluation of commercial ELISA kits for the detection of anti-Plasmodium antibodies in candidate blood donors

Author

Stefano Tais, Valentina D. Mangano, Natalia Tiberti, Massimo Guerriero, Marco Prato, Federica Verra, Fabrizio Bruschi, Francesca Perandin, Lucia Bargagna, Zeno Bisoffi, Franca Migliaccio, and Monica Degani

Subjects
medicine.medical_specialty, Plasmodium, Blood transfusion, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Concordance, medicine.medical_treatment, 030231 tropical medicine, Blood Donors, Enzyme-Linked Immunosorbent Assay, Sensitivity and Specificity, Serology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, parasitic diseases, medicine, Mass Screening, lcsh:RC109-216, 030212 general & internal medicine, ELISA, IFAT, Transfusion transmitted malaria, Retrospective Studies, Italy, Malaria, biology, business.industry, Research, Gold standard (test), medicine.disease, Infectious Diseases, Parasitology, Tropical medicine, biology.protein, Antibody, business
Abstract

Background Transfusion with Plasmodium-infected blood represents a risk for malaria transmission, a rare but severe event. Several non-endemic countries implement a strategy for the screening of candidate blood donors including questionnaire for the identification of at-risk subjects and laboratory testing of blood samples, often serology-based, with temporary deferral from donation for individuals with a positive result. In Italy, the most recent legislation, issued in November 2015, introduced the use of serological tests for the detection of anti-Plasmodium antibodies. Methods In the absence of a gold standard for malaria serology, the aim of this work was to evaluate five commercial ELISA kits, and to determine their accuracy (sensitivity and specificity) in comparison to immuno-fluorescence antibody test (IFAT), and their agreement (concordance of results). Serum samples from malaria patients or from subjects with malaria history (N = 64), malaria naïve patients with other parasitic infections (N = 15), malaria naïve blood donors (N = 8) and malaria exposed candidate blood donors (N = 36) were tested. Results The specificity of all ELISA kits was 100%, while sensitivity ranged between 53 and 64% when compared to IFAT on malaria patients samples. When tested on candidate blood donors’ samples, ELISA kits showed highly variable agreement (42–94%) raising the possibility that the same individual could be included or excluded from donation depending on the test in use by the transfusion centre. Conclusions These preliminary results indicate how the lack of a gold standard for malaria serology must be taken into account in the application and future revision of current legislation. There is need of developing more sensitive serological assays. Moreover, the adoption of a unique serological test at national level is recommended, as well as the development of screening algorithms based on multiple laboratory tests, including molecular assays. Electronic supplementary material The online version of this article (10.1186/s12936-019-2650-0) contains supplementary material, which is available to authorized users.

Published
2019

12. Lack of circulating toxoplasma gondii DNA in seropositive patients with bipolar or schizophrenia spectrum disorders

Author

Valentina D. Mangano, L. Kramer, C. Del Grande, L. Dell'Osso, Isabella Masci, Fabrizio Bruschi, Elisa Schiavi, C. Mangia, Barbara Pinto, L. Rindi, and Luca Galli

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, circulating parasite DNA, nested-PCR, RT-PCR, Toxoplasma gondii, Schizoaffective disorder, Polymerase Chain Reaction, Serology, 03 medical and health sciences, 0302 clinical medicine, Seroepidemiologic Studies, Epidemiology, medicine, Seroprevalence, Humans, Bipolar disorder, Biological Psychiatry, biology, seroprevalence, business.industry, Toxoplasma gondii, seroprevalence, circulating parasite DNA, PCR, nested-PCR, RT-PCR, bipolar disorder, schizoaffective disorder, DNA, Protozoan, Middle Aged, medicine.disease, biology.organism_classification, schizoaffective disorder, Toxoplasmosis, 030227 psychiatry, Psychiatry and Mental health, PCR, Cross-Sectional Studies, Schizophrenia, Case-Control Studies, Immunology, Female, business, Toxoplasma, 030217 neurology & neurosurgery
Abstract

Toxoplasmosis has been previously associated with an increased risk of having Schizophrenia or Bipolar disorder in several epidemiological studies. The aim of this observational, cross-sectional study was to examine the seroprevalence of Toxoplasma infection in a cohort of Italian psychiatric inpatients and to verify the presence of circulating Toxoplasma gondii DNA in the seropositive subjects. Sixty-three patients affected by bipolar or schizoaffective disorders according to DSM-5 criteria were enrolled. The presence of Toxoplasma infection was firstly examined using an indirect serological method (ELFA), and three different direct PCR-based methods were performed to detect circulating DNA in the seropositive patients. The seroprevalence of infection was 28.6%, with a significant association between higher age and the infection status. PCR, nested-PCR and Real-Time PCR revealed no positive samples for Toxoplasma gondii. This result is in contrast with recent data from case-control studies that detected parasite genome in patients with different neuropsychiatric diagnosis without clinical evidence of acute toxoplasmosis. Our findings are to be interpreted with caution, because of the small sample size, the heterogeneity of enrolled patients and the observational nature of the study. Further studies are needed to better define the clinical features correlated to the seropositive status in neuropsychiatric patients.

Published
2018

13. Post-transplant liver graft schistosomiasis in a migrant from Sub-Saharan Africa

Author

Franco Filipponi, Paola Carrai, Luca Pollina, Fabrizio Bruschi, Alessandro Bartoloni, Riccardo Iapoce, Paolo De Simone, Valentina D. Mangano, Luca Giordani, Francesca Rinaldi, and Lorenzo Zammarchi

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Sub saharan, Cirrhosis, medicine.medical_treatment, Schistosomiasis, Liver transplantation, 03 medical and health sciences, Schistosomiasis haematobia, 0302 clinical medicine, schistosomiasis, Internal medicine, parasitic diseases, Medicine, Animals, Humans, 030212 general & internal medicine, Africa South of the Sahara, Schistosoma, Europe, Italy, liver transplantation, migrant, Anthelmintics, Transients and Migrants, Transplantation, biology, business.industry, virus diseases, medicine.disease, biology.organism_classification, Allografts, Post transplant, Liver Transplantation, Liver graft, surgical procedures, operative, Infectious Diseases, Liver, Schistosoma haematobium, 030211 gastroenterology & hepatology, business
Abstract

We report a case of post-transplant liver graft infection with Schistosoma spp in a migrant from sub-Saharan Africa transplanted for HBV-related cirrhosis and with undiagnosed schistosomiasis pre-transplantation. The occurrence of tropical diseases in non-endemic areas warrants screening protocols for organ donors and recipients with a history of exposure in endemic areas.

Published
2018

14. Strength of hydroxide catalysis bonds between sapphire, silicon, and fused silica as a function of time

Author

Arjen Jongschaap, Anna-Maria A. van Veggel, Mariela Masso Reid, J. H. Hough, R. Douglas, M. Phelps, Meghan Kelly, Sheila Rowan, K. Haughian, and Valentina D. Mangano

Subjects
Chemical substance, Silicon, sapphire, fused silica, strength, hydroxide catalysis bonds, silicon, gravitational waves, chemistry.chemical_element, 01 natural sciences, chemistry.chemical_compound, 0103 physical sciences, KAGRA, 010306 general physics, Curing (chemistry), Physics, Einstein Telescope, 010308 nuclear & particles physics, business.industry, GEO600, chemistry, Sapphire, Optoelectronics, Hydroxide, business
Abstract

Hydroxide catalysis bonds have formed an integral part of ground-based gravitational wave (GW) observatories since the 1990s. By allowing the creation of quasimonolithic fused silica mirror suspensions in detectors such as GEO600 and Advanced LIGO, their use was crucial to the first ever direct detection of gravitational waves. Following these successes, this bonding technique has been included in advanced next generation cryogenic detector designs. Currently, they are used to create quasimonolithic crystalline sapphire suspensions in the KAGRA detector. They are also planned for use in silicon suspensions of future detectors such as the Einstein Telescope. In this paper we report how the strength of hydroxide catalysis bonds evolves over time, and compare the curing rates of bonds as they form between fused silica substrates to those between sapphire to sapphire and silicon to silicon substrates. For bonds between all three types of substrate material we show that newly formed bonds exhibit slightly higher breaking stresses than bonds cured for longer periods of time. We find that the strength stabilizes at \ud ≥\ud 15\ud \ud \ud MPa\ud for bonds cured for up to 30 weeks (7 months). This finding is important to future cryogenic GW detector design as it is crucial to ensure the long term integrity of the suspension interfaces. Monitoring the strength of bonds that have been allowed to cure for shorter lengths of time can also shed light on the chemistry of bond formation.

Published
2018

15. Host genetics and parasitic infections

Author

David Modiano and Valentina D. Mangano

Subjects
Microbiology (medical), Candidate gene, trypanosomiasis, Trichuriasis, malaria, Genome-wide association study, Biology, Immune system, schistosomiasis, medicine, Parasitic Diseases, Humans, Genetic Predisposition to Disease, Genetic epidemiology, leishmaniasis, lymphatic filariasis, Genetic Association Studies, Genetics, onchocerciasis, General Medicine, medicine.disease, 3. Good health, Visceral leishmaniasis, Infectious Diseases, genome-wide association studies, soil-transmitted helminth diseases, Immunology, Trypanosomiasis, Malaria
Abstract

Parasites still impose a high death and disability burden on human populations, and are therefore likely to act as selective factors for genetic adaptations. Genetic epidemiological investigation of parasitic diseases is aimed at disentangling the mechanisms underlying immunity and pathogenesis by looking for associations or linkages between loci and susceptibility phenotypes. Until recently, most studies used a candidate gene approach and were relatively underpowered, with few attempts at replicating findings in different populations. However, in the last 5 years, genome-wide and/or multicentre studies have been conducted for severe malaria, visceral leishmaniasis, and cardiac Chagas disease, providing some novel important insights. Furthermore, studies of helminth infections have repeatedly shown the involvement of common loci in regulating susceptibility to distinct diseases such as schistosomiasis, ascariasis, trichuriasis, and onchocherciasis. As more studies are conducted, evidence is increasing that at least some of the identified susceptibility loci are shared not only among parasitic diseases but also with immunological disorders such as allergy or autoimmune disease, suggesting that parasites may have played a role in driving the evolution of the immune system.

Published
2014
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16. Detection of Plasmodium falciparum male and female gametocytes and determination of parasite sex ratio in human endemic populations by novel, cheap and robust RTqPCR assays

Author

Pamela Avellino, Fabrizio Lombardo, Franck Adama Yao, Valentina D. Mangano, Giulia Siciliano, David Modiano, Federica Santolamazza, Pietro Alano, and Jean-Bosco Ouédraogo

Subjects
0301 basic medicine, lcsh:Arctic medicine. Tropical medicine, Gametocytes, Malaria transmission, Plasmodium falciparum, Real Time qPCR, Sex-ratio, lcsh:RC955-962, 030231 tropical medicine, Population Dynamics, Protozoan Proteins, Real-Time Polymerase Chain Reaction, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Burkina Faso, TaqMan, medicine, Gametocyte, Parasite hosting, Humans, lcsh:RC109-216, Genetics, Microscopy, biology, Research, biology.organism_classification, medicine.disease, 3. Good health, Housekeeping gene, 030104 developmental biology, Infectious Diseases, Real-time polymerase chain reaction, Parasitology, Malaria
Abstract

Background: The presence of Plasmodium falciparum gametocytes in peripheral blood is essential for human to mosquito parasite transmission. The detection of submicroscopic infections with gametocytes and the estimation of the gametocyte sex ratio are crucial to assess the human host potential ability to infect mosquitoes and transmit malaria parasites.Aim and objectives: The aim of this work was to develop sensitive and cheap Real Time qPCR assays for large-scale epidemiological surveys, based on detection and amplification of gametocyte sex specific transcripts selected from the literature: the female-specific pfs25 and pf glycerol kinase (pfGK) and the male-specific pfs230p and pf13 transcripts.Methods: RTqPCR assays were used to test the gametocyte- and sex-specific expression of the target genes using asexual stages of the gametocyteless parasite clone F12 and FACS purified male and female gametocytes of the PfDynGFP/P47mCherry line. Assays were performed on 50 blood samples collected during an epidemiological survey in the Soumousso village, Burkina Faso, West-Africa, and amplification of the human housekeeping gene 18S rRNA was employed to normalize RNA sample variability.Results: SYBR Green assays were developed that showed higher sensitivity compared to Taqman assays at a reduced cost. RTqPCR results confirmed that expression of pfs25 and pfs230p are female and male-specific, respectively, and introduced two novel markers, the female-specific pfGK and the male-specific pf13. A formula was derived to calculate the ratio of male to female gametocytes based on the ratio of male to female transcript copy number. Use of these assays in the field samples showed, as expected, a higher sensitivity of RTqPCR compared to microscopy. Importantly, similar values of gametocyte sex-ratio were obtained in the field samples based on the four different target combinations.Conclusion: Novel, sensitive, cheap and robust molecular assays were developed for the detection and quantification of female and male P. falciparum gametocytes. In particular, the RTqPCR assays based on the female-specific pfs25 and the newly described male gametocyte-specific pf13 transcripts, including normalization by the human 18S, reliably assess presence and abundance of female and male gametocytes and enable to determine their sex-ratio in human subjects in endemic areas.

Published
2017

17. Reappraisal of known malaria resistance loci in a large multicenter study

Author

Malcolm E. Molyneux, Peter Siba, Andre Ndi, Valentina D. Mangano, Cao Quang Thai, Vysaul Nyirongo, Subulade A. Olaniyan, Angie Green, Mahamadou A. Thera, Timothy M. E. Davis, Síle F. Molloy, Kathryn Fitzpatrick, Giorgio Sirugo, Edith C. Bougouma, Chris Drakeley, Anthony Enimil, Angela Allen, Olukemi K. Amodu, Christina Hubbart, Nuno Sepúlveda, Nguyen Hoan Phu, M Jallow, Carolyne M. Ndila, Stanley Usen, Kimberly J. Johnson, Hugh Reyburn, Taane G. Clark, Dominic P. Kwiatkowski, Si Quang Le, Tobias O. Apinjoh, Kalifa Bojang, Jennifer R Evans, Michael D. Wilson, Lee Hart, Sophie Uyoga, Angeliki Kerasidou, Eric A. Achidi, Steve Allen, Kirk A. Rockett, Pascal Michon, Ivo Mueller, Anna E. Jeffreys, Belco Poudiougou, Anita Ghansah, Norbert Peshu, Fatoumatta Sisay-Joof, David Kachala, Sodiomon B. Sirima, David J. Conway, Geraldine M. Clarke, Regina N. Mugri, Moses Laman, Aaron Vanderwal, Miguel A. Sanjoaquin, Sibiry Sissoko, Ousmane Touré, Laurens Manning, Chris C. A. Spencer, Matti Pirinen, David Modiano, Sarah J. Dunstan, Harin Karunajeewa, Alexander Macharia, Tran Tinh Hien, Tsiri Agbenyega, Gavin Band, Kate Rowlands, Salimata Konate, Rachel Craik, L. Amenga-Etego, Nguyen Ngoc Quyen, Kwadwo A. Koram, Amadou Niangaly, Margaret Pinder, Alphaxard Manjurano, Terrie E. Taylor, Ogobara K. Doumbo, Eleanor M. Riley, Jeremy Farrar, Victoria Cornelius, Kevin Marsh, and Thomas N. Williams

Subjects
medicine.medical_specialty, Genome-wide association study, Glucosephosphate Dehydrogenase, Polymorphism, Single Nucleotide, Article, Papua New Guinea, Plasma Membrane Calcium-Transporting ATPases, Polymorphism (computer science), ABO blood group system, parasitic diseases, Epidemiology, Genetics, medicine, Humans, Malaria, Falciparum, Africa South of the Sahara, Genetic Association Studies, Disease Resistance, biology, Transmission (medicine), Case-control study, Plasmodium falciparum, medicine.disease, biology.organism_classification, 3. Good health, Glucosephosphate Dehydrogenase Deficiency, Logistic Models, Vietnam, Genetic Loci, Case-Control Studies, Malaria
Abstract

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Published
2014

18. Resistance to malaria through structural variation of red blood cell invasion receptors

Author

Kate Rowlands, Eleanor M. Riley, David Modiano, David Kachala, Nicole Thornton, Muminatou Jallow, Edith C. Bougouma, Anna E. Jeffreys, Carolyne M. Ndila, Jim Stalker, Tobias O. Apinjoh, Eleanor Drury, Malcolm E. Molyneux, Alphaxard Manjurano, Ellen M. Leffler, Chris Drakeley, Shane Grimsley, Louise Tilley, George B.J. Busby, Victoria Cornelius, Kevin Marsh, Vysaul Nyirongo, Thomas N. Williams, Geraldine M. Clarke, Terrie Taylor, Fatoumatta Sisay-Joof, Christina Hubbart, Valentina D. Mangano, Kalifa Bojang, Sodiomon B. Sirima, David J. Conway, Katja Kivinen, Hugh Reyburn, Dominic P. Kwiatkowski, Norbert Peshu, Quang Si Le, Eric A. Achidi, Kirk A. Rockett, Chris C. A. Spencer, Gavin Band, Wellcome Trust, and Commission of the European Communities

Subjects
0301 basic medicine, Models, Molecular, Erythrocytes, Protein Structure, Secondary, 0302 clinical medicine, Gene Frequency, Glycophorins, Copy-number variation, Malaria, Falciparum, Child, Disease Resistance, Genetics, 0303 health sciences, Multidisciplinary, GYPA, biology, GYPB, Research Support, Non-U.S. Gov't, Medicine (all), 3. Good health, Multidisciplinary Sciences, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Malaria Genomic Epidemiology Network, Glycophorin, Adult, multidisciplinary, antigens, cells rbcs, DNA Copy Number Variations, General Science & Technology, Locus (genetics), Receptors, Cell Surface, Host-Parasite Interactions, Structural variation, 03 medical and health sciences, Research Support, N.I.H., Extramural, parasitic diseases, Journal Article, medicine, Humans, 1000 Genomes Project, Gene, Africa South of the Sahara, 030304 developmental biology, Science & Technology, Genome, Human, Haplotype, Plasmodium falciparum, biology.organism_classification, medicine.disease, Red blood cell, 030104 developmental biology, biology.protein, Malaria
Abstract

INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells. In the case of Plasmodium falciparum , this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa. This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system. In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors. RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa. To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus. RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region. In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity. By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association. In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria. To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure. The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA. Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant. CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive. Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus. Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria. This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease.

Published
2016

19. Author response: Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Author

Gavin Band, Salimata Konate, Muminatou Jallow, Thomas N. Williams, Sibiry Sissoko, Nguyen Hoan Phu, Hugh Reyburn, Nuno Sepúlveda, Ousmane Touré, Christina Hubbart, Chris Drakeley, Dominic P. Kwiatkowski, Sophie Uyoga, Regina N. Mugri, Ivo Mueller, Anna E. Jeffreys, Timothy M. E. Davis, Olukemi K. Amodu, Lee Hart, Geraldine M. Clarke, Anita Ghansah, Eleanor M. Riley, Ogobara K. Doumbo, Kate Rowlands, Tobias O. Apinjoh, Eric A. Achidi, Steve Allen, Kirk A. Rockett, Fatoumatta Sisay-Joof, Síle F. Molloy, Taane G. Clark, Jeremy Farrar, Valentina D. Mangano, Victoria Cornelius, Kevin Marsh, Shivang S. Shah, Kalifa Bojang, Vysaul Nyirongo, Pascal Michon, Alexander Macharia, Angela Allen, Peter Siba, Cao Quang Thai, Carolyne M. Ndila, Subulade A. Olaniyan, Stanley Usen, Andre Ndi, Laurens Manning, Jennifer Evans, Chris C. A. Spencer, Mahamadou A. Thera, Margaret Pinder, Malcolm E. Molyneux, David Kachala, Alphaxard Manjurano, Norbert Peshu, Terrie E. Taylor, Amadou Niangaly, Moses Laman, Katja Kivinen, Tsiri Agbenyega, Lucas Amenga-Etego, Edith C. Bougouma, Nguyen Ngoc Quyen, Giorgio Sirugo, Anthony Enimil, David Modiano, Angeliki Kerasidou, Tran Tinh Hien, Michael D. Wilson, Susana Campino, Sodiomon B. Sirima, David J. Conway, Sarah J. Dunstan, Kwadwo A. Koram, Harin Karunajeewa, and Belco Poudiougou

Subjects
Cerebral Malaria, business.industry, Immunology, Medicine, business
Published
2016

20. An effective method to purify Plasmodium falciparum DNA directly from clinical blood samples for whole genome high-throughput sequencing

Author

Daniel Alcock, Elisa Anastasi, Jean-Bosco Ouédraogo, Kirk A. Rockett, Ogobara K. Doumbo, Abdoulaye Djimde, Gareth Maslen, Valentina D. Mangano, Magnus Manske, Bronwyn MacInnis, David Modiano, Sarah Auburn, Chris I. Newbold, Taane G. Clark, Dominic P. Kwiatkowski, Issaka Zongo, Susana Campino, Robert Pinches, and Dimopoulos, G

Subjects
Immune Cells, 030231 tropical medicine, Plasmodium falciparum, lcsh:Medicine, Biology, Mali, Parasitemia, Genome, DNA sequencing, Monocytes, Lymphocyte Depletion, 03 medical and health sciences, 0302 clinical medicine, Diagnostic Medicine, Burkina Faso, parasitic diseases, Parasitic Diseases, Leukocytes, Humans, Genome Sequencing, lcsh:Science, 030304 developmental biology, Whole genome sequencing, Genetics, 0303 health sciences, Multidisciplinary, Massive parallel sequencing, Shotgun sequencing, lcsh:R, Tropical Diseases (Non-Neglected), High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, DNA, Protozoan, DNA extraction, Clinical Laboratory Sciences, Malaria, genomic DNA, Infectious Diseases, Medicine, Clinical Immunology, lcsh:Q, Blood sampling, Research Article
Abstract

Highly parallel sequencing technologies permit cost-effective whole genome sequencing of hundreds of Plasmodium parasites. The ability to sequence clinical Plasmodium samples, extracted directly from patient blood without a culture step, presents a unique opportunity to sample the diversity of "natural" parasite populations in high resolution clinical and epidemiological studies. A major challenge to sequencing clinical Plasmodium samples is the abundance of human DNA, which may substantially reduce the yield of Plasmodium sequence. We tested a range of human white blood cell (WBC) depletion methods on P. falciparum-infected patient samples in search of a method displaying an optimal balance of WBC-removal efficacy, cost, simplicity, and applicability to low resource settings. In the first of a two-part study, combinations of three different WBC depletion methods were tested on 43 patient blood samples in Mali. A two-step combination of Lymphoprep plus Plasmodipur best fitted our requirements, although moderate variability was observed in human DNA quantity. This approach was further assessed in a larger sample of 76 patients from Burkina Faso. WBC-removal efficacy remained high (70% samples) and lower variation was observed in human DNA quantities. In order to assess the Plasmodium sequence yield at different human DNA proportions, 59 samples with up to 60% human DNA contamination were sequenced on the Illumina Genome Analyzer platform. An average 40-fold coverage of the genome was observed per lane for samples with ≤ 30% human DNA. Even in low resource settings, using a simple two-step combination of Lymphoprep plus Plasmodipur, over 70% of clinical sample preparations should exhibit sufficiently low human DNA quantities to enable 40-fold sequence coverage of the P. falciparum genome using a single lane on the Illumina Genome Analyzer platform. This approach should greatly facilitate large-scale clinical and epidemiologic studies of P. falciparum.

Published
2016

21. Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations

Author

Mahamadou Diakite, Kevin Marsh, David Modiano, Malcolm E. Molyneux, Terrie E. Taylor, Norbert Peshu, Fatou Sisay-Joof, Andrew E. Fry, Anna Richardson, Dominic P. Kwiatkowski, Thomas N. Williams, Sarah Auburn, Valentina D. Mangano, Charles R. Newton, Angela Green, Margaret Pinder, Kirk A. Rockett, Susana Campino, Michael J. Griffiths, Muminatou Jallow, and Taane G. Clark

Subjects
Parents, Malawi, qw_541, Pediatrics and Child Health, lcsh:Medicine, 0302 clinical medicine, Genotype, lcsh:Science, Child, Genetics, qw_553, 0303 health sciences, qw_552, Multidisciplinary, qw_551, 3. Good health, wc_695, Infectious Diseases, Cerebral Malaria, Gambia, qu_450, Research Article, Adult, qw_563, wc_680, wa_115, Immunology, Single-nucleotide polymorphism, Locus (genetics), wa_395, Biology, wc_765, Polymorphism, Single Nucleotide, wa_110, Young Adult, 03 medical and health sciences, wb_710, Genetic variation, parasitic diseases, medicine, Humans, 030304 developmental biology, Family Health, lcsh:R, Haplotype, Genetics and Genomics, Plasmodium falciparum, wc_755, medicine.disease, biology.organism_classification, Kenya, Malaria, wc_750, qx_135, Africa, lcsh:Q, 030217 neurology & neurosurgery, Interferon Regulatory Factor-1
Abstract

Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.

Published
2016

22. Admixture into and within sub-Saharan Africa

Author

Angeliki Kerasidou, J O'Brien, Aaron Vanderwal, Christina Hubbart, Alistair Miles, Catherine L. Moyes, A Nyika, Abier Elzein, J Shelton, Spencer Cca., Anthony Enimil, A Diss, C Hughes, Lucas Amenga-Etego, E Somaskantharajah, Ogobara K. Doumbo, Jacob Almagro Garcia, Valentina D. Mangano, E Drury, Edith Bougama, Angie Green, Busby Gbj., Geraldine M. Clarke, Dominic P. Kwiatkowski, Jiannis Ragoussis, Alphaxard Manjurano, Bronwyn MacInnis, Tobias O. Apinjoh, D Mead, Gareth Maslen, George B.J. Busby, Kirk A. Rockett, Dushyanth Jyothi, C Potter, C Malangone, Muminatou Jallow, I Ragoussis, Ellen M. Leffler, J Rogers, J Stalker, Quang Si Le, J Rodford, D Barnwell, Alieu Mendy, J deVries, Anna E. Jeffreys, Carolyne M. Ndila, E Hilton, Vysaul Nyirongo, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Medical Research Council Unit The Gambia (MRC), Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), Komfo Anokye Teaching Hospital, University of Buéa, KEMRI-Wellcome Trust Research Programme (KWTRP), London School of Hygiene and Tropical Medicine (LSHTM), University of Malawi, University of Bamako [Mali], Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Wellcome Trust, Medical Research Council, Foundation for the National Institutes of Health, Malaria Genomics Epidemiology Network : Vanderwal A, Elzein A, Nyika A, Mendy A, Miles A, Diss A, Kerasidou A, Green A, Jeffreys AE, MacInnis B, Hughes C, Moyes C, Spencer CC, Hubbart C, Malangone C, Potter C, Mead D, Barnwell D, Kwiatkowski DP, Jyothi D, Drury E, Somaskantharajah E, Hilton E, Leffler E, Maslen G, Band G, Busby G, Clarke GM, Ragoussis I, Garcia JA, Rogers J, deVries J, Shelton J, Ragoussis J, Stalker J, Rodford J, O'Brien J, Evans J, Rowlands K, Cook K, Fitzpatrick K, Kivinen K, Small K, Johnson KJ, Rockett KA, Hart L, Manske M, McCreight M, Stevens M, Pirinen M, Hennsman M, Parker M, SanJoaquin M, Seplúveda N, Cook O, Miotto O, Deloukas P, Craik R, Wrigley R, Watson R, Pearson R, Hutton R, Oyola S, Auburn S, Shah S, Le SQ, Molloy S, Bull S, Campino S, Clark TG, Ruano-Rubio V, Cornelius V, Teo YY, Corran P, Silva ND, Risley P, Doyle A, Evans J, Horstmann R, Plowe C, Duffy P, Carucci D, Gottleib M, Tall A, Ly AB, Dolo A, Sakuntabhai A, Puijalon O, Bah A, Camara A, Sadiq A, Khan AA, Jobarteh A, Mendy A, Ebonyi A, Danso B, Taal B, Casals-Pascual C, Conway DJ, Onykwelu E, Sisay-Joof F, Sirugo G, Kanyi H, Njie H, Obu H, Saine H, Sambou I, Abubakar I, Njie J, Fullah J, Jaiteh J, Bojang KA, Jammeh K, Sabally-Ceesay K, Manneh L, Camara L, Yamoah L, Njie M, Njie M, Pinder M, Jallow M, Aiyegbo M, Jasseh M, Keita ML, Saidy-Khan M, Jallow M, Ceesay N, Rasheed O, Ceesay PL, Esangbedo P, Cole-Ceesay R, Olaosebikan R, Correa S, Njie S, Usen S, Dibba Y, Barry A, Djimdé A, Sall AH, Abathina A, Niangaly A, Dembele A, Poudiougou B, Diarra E, Bamba K, Thera MA, Doumbo O, Toure O, Konate S, Sissoko S, Diakite M, Konate AT, Modiano D, Bougouma EC, Bancone G, Ouedraogo IN, Simpore J, Sirima SB, Mangano VD, Troye-Blomberg M, Oduro AR, Hodgson AV, Ghansah A, Nkrumah F, Atuguba F, Koram KA, Amenga-Etego LN, Wilson MD, Ansah NA, Mensah N, Ansah PA, Anyorigiya T, Asoala V, Rogers WO, Akoto AO, Ofori AO, Enimil A, Ansong D, Sambian D, Asafo-Agyei E, Sylverken J, Antwi S, Agbenyega T, Orimadegun AE, Amodu FA, Oni O, Omotade OO, Amodu O, Olaniyan S, Ndi A, Yafi C, Achidi EA, Mbunwe E, Anchang-Kimbi J, Mugri R, Besingi R, Apinjoh TO, Titanji V, Elhassan A, Hussein A, Mohamed H, Elhassan I, Ibrahim M, Kokwaro G, Oluoch T, Macharia A, Ndila CM, Newton C, Opi DH, Kamuya D, Bauni E, Marsh K, Peshu N, Molyneux S, Uyoga S, Williams TN, Marsh V, Manjurano A, Nadjm B, Maxwell C, Drakeley C, Riley E, Mtei F, Mtove G, Wangai H, Reyburn H, Joseph S, Ishengoma D, Lemnge M, Mutabingwa T, Makani J, Cox S, Phiri A, Munthali A, Kachala D, Njiragoma L, Molyneux ME, Moore M, Ntunthama N, Pensulo P, Taylor T, Nyirongo V, Carter R, Fernando D, Karunaweera N, Dewasurendra R, Suriyaphol P, Singhasivanon P, Simmons CP, Thai CQ, Sinh DX, Farrar J, Chuong LV, Phu NH, Hieu NT, Hoang Mai NT, Ngoc Quyen NT, Day N, Dunstan SJ, O'Riordan SE, Hong Chau TT, Hien TT, Allen A, Lin E, Karunajeewa H, Mueller I, Reeder J, Manning L, Laman M, Michon P, Siba P, Allen S, Davis TM., Commission of the European Communities, and Wellcome Trust

Subjects
0301 basic medicine, Population genetics, Gene flow, 0302 clinical medicine, MESH: Genetic Variation, Biology (General), African Continental Ancestry Group, media_common, Genetics, 0303 health sciences, education.field_of_study, Human migration, General Neuroscience, 030305 genetics & heredity, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Geography, Genomics and Evolutionary Biology, MESH: Human Migration, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, admixture, gene-flow, Research Article, Gene Flow, QH301-705.5, Science, media_common.quotation_subject, Human Migration, Population, Black People, Genomics, Biology, africa, chromosome painting, evolutionary biology, genomics, human, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Genetic variation, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, MESH: Africa South of the Sahara, Allele, education, Africa South of the Sahara, MESH: Gene Flow, MESH: Genome, Human, 030304 developmental biology, Genetic diversity, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], General Immunology and Microbiology, business.industry, Genome, Human, Haplotype, Genetic Variation, MESH: Haplotypes, 030104 developmental biology, Genetic epidemiology, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Agriculture, Evolutionary biology, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: African Continental Ancestry Group, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Demography, Diversity (politics)
Abstract

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology. DOI: http://dx.doi.org/10.7554/eLife.15266.001, eLife digest Our genomes contain a record of historical events. This is because when groups of people are separated for generations, the DNA sequence in the two groups’ genomes will change in different ways. Looking at the differences in the genomes of people from the same population can help researchers to understand and reconstruct the historical interactions that brought their ancestors together. The mixing of two populations that were previously separate is known as admixture. Africa as a continent has few written records of its history. This means that it is somewhat unknown which important movements of people in the past generated the populations found in modern-day Africa. Busby et al. have now attempted to use DNA to look into this and reconstruct the last 4000 years of genetic history in African populations. As has been shown in other regions of the world, the new analysis showed that all African populations are the result of historical admixture events. However, Busby et al. could characterize these events to unprecedented level of detail. For example, multiple ethnic groups from The Gambia and Mali all show signs of sharing the same set of ancestors from West Africa, Europe and Asia who mixed around 2000 years ago. Evidence of a migration of people from Central West Africa, known as the Bantu expansion, could also be detected, and was shown to carry genes to the south and east. An important next step will be to now look at the consequences of the observed gene-flow, and ask if it has contributed to spreading beneficial, or detrimental, mutations around Africa. DOI: http://dx.doi.org/10.7554/eLife.15266.002

Published
2016

23. Author response: Admixture into and within sub-Saharan Africa

Author

Chris C. A. Spencer, Ogobara Doumba, Valentina D. Mangano, Carolyne M. Ndila, Quang Si Le, Gavin Band, George B.J. Busby, Edith Bougama, Tobias O. Apinjoh, Muminatou Jallow, Kirk A. Rockett, Vysaul Nyirongo, Alphaxard Manjurano, Anthony Enimil, Dominic P. Kwiatkowski, and Lucas Amenga-Etego

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Geography, Sub saharan, Socioeconomics
Published
2016

24. Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study

Author

Magnus Manske, Taane Clark, Deus Ishengoma, Valentina D Mangano, Kerrin Small, Issa Nebie, Dushyanth Jyothi, Catherine Moyes, Katja Kivinen, George Mtove, Dominic Kwiatkowski, Jacques Simporé, Behzad Nadjm, Adebola Orimadegun, Kalifa Bojang, Panos Deloukas, Nadira Karunaweera, Kimberly J Johnson, Mahamadou A Thera, Gareth Maslen, Nuno Sepúlveda, Daniel Mead, Sophie Uyoga, Tobias Apinjoh, John Reeder, Lee Hart, Climent Casals-Pascual, Sarah Auburn, Sharon Cox, KEMRI-Wellcome Trust Research Programme (KWTRP), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Imperial College London, Institut Pasteur [Paris], TNW is funded by the Wellcome Trust (091758) and DPK receives support from the UK Medical Research Council (G19/9). SS is supported by the Medical Scientist Training Program at the US National Institutes of Health and received travel funds from Wolfson College, Oxford, and from the Oxford University Exploration Club. This research received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095 and from the UK Medical Research Council (G0600718). The MalariaGEN Project is supported by the Wellcome Trust (077383) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative and through a Wellcome Trust Strategic Award (090770). The Wellcome Trust provides core support to The KEMRI–Wellcome Trust Research Programme in Kilifi (084535) and the Wellcome Trust Centre for Human Genetics (090532), Oxford, UK., the MalariaGEN Consortium: members listed at http://www.malariagen.net/projects/host/consortium-members, European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009), University of Oxford, and Institut Pasteur [Paris] (IP)

Subjects
Male, Pediatrics, Rate ratio, Cohort Studies, Risk Factors, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Child, MESH: Cohort Studies, media_common, MESH: Heterozygote, 2. Zero hunger, hematology, Incidence (epidemiology), 1. No poverty, Articles, glucosephosphate dehydrogenase deficiency, glucosephosphate dehydrogenase, glucose-6-phosphate dehydrogenase, MESH: Case-Control Studies, MESH: Infant, 3. Good health, MESH: Glucosephosphate Dehydrogenase Deficiency, Child, Preschool, Female, Cohort study, Heterozygote, medicine.medical_specialty, Adolescent, MESH: Kenya, MESH: Malaria, parasitic diseases, medicine, MESH: United States, Humans, media_common.cataloged_instance, European union, MESH: Adolescent, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Child, Preschool, Case-control study, Infant, Odds ratio, medicine.disease, Kenya, United States, MESH: Male, Malaria, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, Glucose-6-phosphate dehydrogenase deficiency
Abstract

Summary Background The global prevalence of X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be a result of selection by malaria, but epidemiological studies have yielded confusing results. We investigated the relationships between G6PD deficiency and both malaria and non-malarial illnesses among children in Kenya. Methods We did this study in Kilifi County, Kenya, where the G6PD c.202T allele is the only significant cause of G6PD deficiency. We tested the associations between G6PD deficiency and severe and complicated Plasmodium falciparum malaria through a case-control study of 2220 case and 3940 control children. Cases were children aged younger than 14 years, who visited the high dependency ward of Kilifi County Hospital with severe malaria between March 1, 1998, and Feb 28, 2010. Controls were children aged between 3–12 months who were born within the same study area between August 2006, and September 2010. We assessed the association between G6PD deficiency and both uncomplicated malaria and other common diseases of childhood in a cohort study of 752 children aged younger than 10 years. Participants of this study were recruited from a representative sample of households within the Ngerenya and Chonyi areas of Kilifi County between Aug 1, 1998, and July 31, 2001. The primary outcome measure for the case-control study was the odds ratio for hospital admission with severe malaria (computed by logistic regression) while for the cohort study it was the incidence rate ratio for uncomplicated malaria and non-malaria illnesses (computed by Poisson regression), by G6PD deficiency category. Findings 2863 (73%) children in the control group versus 1643 (74%) in the case group had the G6PD normal genotype, 639 (16%) versus 306 (14%) were girls heterozygous for G6PD c.202T, and 438 (11%) versus 271 (12%) children were either homozygous girls or hemizygous boys. Compared with boys and girls without G6PD deficiency, we found significant protection from severe malaria (odds ratio [OR] 0·82, 95% CI 0·70–0·97; p=0·020) among G6PD c.202T heterozygous girls but no evidence for protection among G6PD c.202T hemizygous boys and homozygous girls (OR 1·18, 0·99–1·40; p=0·056). Median follow-up for the mild disease cohort study was 2·24 years (IQR 2·22–2·85). G6PD c.202T had no effect on other common diseases of childhood in heterozygous girls (incidence rate ratio 0·98, 95% CI 0·86–1·11; p=0·82) or homozygous girls or hemizygous boys (0·93, 0·82–1·04; p=0·25), with the sole exception of a marginally significant increase in the incidence of helminth infections among heterozygous girls. Interpretation Heterozygous girls might be the driving force for the positive selection of G6PD deficiency alleles. Further studies are needed to definitively establish the mechanisms by which G6PD deficiency confers an advantage against malaria in heterozygous individuals. Such studies could lead to the development of new treatments. Funding Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health (as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative).

Published
2015

25. Differential antibody response to the Anopheles gambiae gSG6 and cE5 salivary proteins in individuals naturally exposed to bites of malaria vectors

Author

David Modiano, Valentina D. Mangano, Sodiomon B. Sirima, Issa Nebie, Gabriella Fiorentino, Raffaele Ronca, Bruno Arcà, Cinzia Rizzo, Fabrizio Lombardo, Rizzo, C, Lombardo, F, Ronca, R, Mangano, V, Sirima, S, Nèbiè, I, Fiorentino, Gabriella, Modiano, D, and Arcà, B.

Subjects
Saliva, IgG, Anopheles gambiae, 030231 tropical medicine, Pilot Projects, Colombia, Immunoglobulin G, Anopheles gambiae, Salivary proteins, Immune response, IgG, IgG1, IgG4, Marker of exposure, Plasmodium transmission, Malaria epidemiology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, parasitic diseases, Anopheles, medicine, Salivary proteins, Immune response, IgG1, IgG4, Marker of exposure, Plasmodium transmission, Malaria epidemiology, Animals, Humans, Chile, Salivary Proteins and Peptides, 030304 developmental biology, 0303 health sciences, biology, Research, medicine.disease, biology.organism_classification, United States, 3. Good health, Insect Vectors, Malaria, Infectious Diseases, Immunology, biology.protein, Insect Proteins, Parasitology, Antibody, Animal Distribution
Abstract

Background Mosquito saliva plays crucial roles in blood feeding but also evokes in hosts an anti-saliva antibody response. The IgG response to the Anopheles gambiae salivary protein gSG6 was previously shown to be a reliable indicator of human exposure to Afrotropical malaria vectors. We analyzed here the humoral response to the salivary anti-thrombin cE5 in a group of individuals from a malaria hyperendemic area of Burkina Faso. Methods ELISA was used to measure the anti-cE5 IgG, IgG1 and IgG4 antibody levels in plasma samples collected in the village of Barkoumbilen (Burkina Faso) among individuals of the Rimaibé ethnic group. Anti-gSG6 IgG levels were also determined for comparison. Anopheles vector density in the study area was evaluated by indoor pyrethrum spray catches. Results The cE5 protein was highly immunogenic and triggered in exposed individuals a relatively long-lasting antibody response, as shown by its unchanged persistence after a few months of absent or very low exposure (dry season). In addition cE5 did not induce immune tolerance, as previously suggested for the gSG6 antigen. Finally, IgG subclass analysis suggested that exposed individuals may mount a Th1-type immune response against the cE5 protein. Conclusions The anti-cE5 IgG response is shown here to be a sensitive indicator of human exposure to anopheline vectors and to represent an additional tool for malaria epidemiological studies. It may be especially useful in conditions of low vector density, to monitor transiently exposed individuals (i.e. travellers/workers/soldiers spending a few months in tropical Africa) and to evaluate the impact of insecticide treated nets on vector control. Moreover, the gSG6 and cE5 salivary proteins were shown to trigger in exposed individuals a strikingly different immune response with (i) gSG6 evoking a short-lived IgG response, characterized by high IgG4 levels and most likely induction of immune tolerance, and (ii) cE5 eliciting a longer-living IgG response, dominated by anti-cE5 IgG1 antibodies and not inducing tolerance mechanisms. We believe that these two antigens may represent useful reagents to further investigate the so far overlooked role of Anopheles saliva and salivary proteins in host early immune response to Plasmodium parasites. Electronic supplementary material The online version of this article (doi:10.1186/s13071-014-0549-8) contains supplementary material, which is available to authorized users.

Published
2014

26. An evolutionary perspective of how infection drives human genome diversity: the case of malaria

Author

Valentina D. Mangano and David Modiano

Subjects
Genetics, Plasmodium, biology, Genome, Human, Immunology, Haptoglobin, Locus (genetics), medicine.disease, Adaptation, Physiological, Malaria, Evolution, Molecular, Convergent evolution, medicine, biology.protein, Immunology and Allergy, Epistasis, Parasite hosting, Animals, Humans, Human genome, Alleles, Genetic association
Abstract

Infection with malaria parasites has imposed a strong selective pressure on the human genome, promoting the convergent evolution of a diverse range of genetic adaptations, many of which are harboured by the red blood cell, which hosts the pathogenic stage of the Plasmodium life cycle. Recent genome-wide and multi-centre association studies of severe malaria have consistently identified ATP2B4 , encoding the major Ca 2+ pump of erythrocytes, as a novel resistance locus. Evidence is also accumulating that interaction occurs among resistance loci, the most recent example being negative epistasis among alpha-thalassemia and haptoglobin type 2. Finally, studies on the effect of haemoglobin S and C on parasite transmission to mosquitoes have suggested that protective variants could increase in frequency enhancing parasite fitness.

Published
2014

27. IgG1 and IgG4 antibody responses to the Anopheles gambiae salivary protein gSG6 in the sympatric ethnic groups Mossi and Fulani in a malaria hyperhendemic area of Burkina Faso

Author

David Modiano, Gabriella Fiorentino, Bruno Arcà, Issa Nebie, Raffaele Ronca, Sodiomon B. Sirima, Valentina D. Mangano, Cinzia Rizzo, Marita Troye-Blomberg, Fabrizio Lombardo, Rizzo, C, Ronca, R, Lombardo, F, Mangano, V, Sirima, Sb, Nèbiè, I, Fiorentino, Gabriella, Troye Blomberg, M, Modiano, D, and Arcà, B.

Subjects
Epidemiology, Anopheles gambiae, Protozoan Proteins, lcsh:Medicine, Disease Vectors, Biochemistry, Mosquitoes, Immunoglobulin G, Immune tolerance, ADULT FEMALE MOSQUITO, PLASMODIUM-FALCIPARUM MALARIA, AEDES-AEGYPTI, GLAND TRANSCRIPTS, HUMORAL RESPONSE, IMMUNE-RESPONSE, TROPICAL AFRICA, ANTIGENS, MARKER, INFECTION, Allergies, Medicine and Health Sciences, Malaria, Falciparum, lcsh:Science, Child, Immune Response, Multidisciplinary, Immune System Proteins, biology, 3. Good health, Circumsporozoite protein, Insects, Infectious Diseases, saliva protein, Insect Proteins, Antibody, Research Article, Adult, Adolescent, Arthropoda, Immunology, Black People, Antibodies, Young Adult, Immune system, Antigen, parasitic diseases, Anopheles, Burkina Faso, medicine, Immune Tolerance, Parasitic Diseases, Animals, Humans, Salivary Proteins and Peptides, lcsh:R, Immunity, Organisms, Biology and Life Sciences, Proteins, medicine.disease, biology.organism_classification, Virology, Invertebrates, Malaria, Biomarker Epidemiology, biology.protein, lcsh:Q, Clinical Immunology, immunoglobulin
Abstract

Human antibody response to the Anopheles gambiae salivary protein gSG6 has recently emerged as a potentially useful tool for malaria epidemiological studies and for the evaluation of vector control interventions. However, the current understanding of the host immune response to mosquito salivary proteins and of the possible crosstalk with early response to Plasmodium parasites is still very limited. We report here the analysis of IgG1 and IgG4 subclasses among anti-gSG6 IgG responders belonging to Mossi and Fulani from Burkina Faso, two ethnic groups which are known for their differential humoral response to parasite antigens and for their different susceptibility to malaria. The IgG1 antibody response against the gSG6 protein was comparable in the two groups. On the contrary, IgG4 titers were significantly higher in the Fulani where, in addition, anti-gSG6 IgG4 antibodies appeared in younger children and the ratio IgG4/IgG1 stayed relatively stable throughout adulthood. Both gSG6-specific IgG1 and IgG4 antibodies showed a tendency to decrease with age whereas, as expected, the IgG response to the Plasmodium circumsporozoite protein (CSP) exhibited an opposite trend in the same individuals. These observations are in line with the idea that the An. gambiae gSG6 salivary protein induces immune tolerance, especially after intense and prolonged exposure as is the case for the area under study, suggesting that gSG6 may trigger in exposed individuals a Th2-oriented immune response.

Published
2014

28. Search for gravitational wave ringdowns from perturbed intermediate mass black holes in LIGO-Virgo data from 2005?2010

Author

Li-Wei Wei, Kenneth A. Strain, Fabio Marchesoni, Kyungmin Kim, G. Quiroga, Yi Pan, K. E. Ramirez, Michael L. Gorodetsky, Michaela Pickenpack, Simon Stevenson, David Hammer, Joseph O'Dell, Hartmut Grote, G. Losurdo, Albrecht Ruediger, Neil J. Cornish, Peter Aufmuth, Jiayi Qin, Sammanani S. Premachandra, Jamie Scott, V. Re, Bruce Gendre, Robinjeet Singh, M. Yvert, T. D. Abbott, Jong H. Chow, Ludovico Carbone, P. Couvares, Benno Willke, J. Bauchrowitz, F. Garufi, Cristina Torres, Denis Martynov, S. G. Crowder, Federico Ferrini, Marco Colombini, A. F. Brooks, Q. Chu, Szymon Steplewski, Gerardo Moreno, Chunnong Zhao, J. Macarthur, Karen Roland, G. Vajente, David H. Shoemaker, M. Tse, D. M. Macleod, M. Meinders, W. D. Vousden, Gianpietro Cagnoli, L. Wallace, J. Poeld, R. Frey, Christophe Collette, Zhixing Yang, Evan Ochsner, Vicky Kalogera, Larry R. Price, Elaine Rhoades, Adrien Le Roux, Ajay Kumar, M. Leonardi, Carl Adams, C. Belczynski, M. A. Barton, Alessandra Buonanno, Brian O'Reilly, D. B. Kelley, Matteo Lorenzini, Linqing Wen, S. E. Zuraw, C. Palomba, R. Chakraborty, B. L. Swinkels, D. Verkindt, G. Kang, Christelle Buy, César A. Costa, Xing Zhu, S. Privitera, F. Vetrano, M. K. Haris, T. Vo, C. Bradaschia, P. Oppermann, Michele Vallisneri, M. S. Shahriar, Joris van Heijningen, Sascha Husa, Sonali Mohapatra, P. T. Beyersdorf, Andrew Lundgren, Eliu Huerta, Szabolcs Marka, Timothy A Welborn, M. T. Hartman, V. Kringel, Marica Branchesi, N. Straniero, Alessio Rocchi, D. R. Ingram, Ryan Fisher, Ivan Maksimovic, K. Siellez, A. Conte, Steffen Kaufer, Jo van den Brand, Daniel Amariutei, Saps Buchman, L. Sammut, A. Ain, D. Bersanetti, K. Mailand, K. A. Hodge, Marilyne Andersen, Mauro Tonelli, Kip S. Thorne, T. Chalermsongsak, Alessandro Bertolini, Duncan Meacher, B. Shapiro, Jonathan F. Stebbins, Heinz-Bernd Eggenstein, Zhihui Du, V. P. Mitrofanov, Sanjit Mitra, R. Mittleman, Sharad Gaonkar, Ik Siong Heng, Cyrus Reed, T. Z. Summerscales, Nelson Christensen, Sunil Susmithan, Oliver Puncken, Tyson Littenberg, D. Lodhia, Neil Gehrels, R. Lynch, V. Boschi, Hee Cho, Kasem Mossavi, Deepak Nanda Kumar, Grant David Meadors, R. Coyne, Haixing Miao, S. L. Danilishin, G. Bogaert, M. Shaltev, D. C. Coyne, J. Aasi, Jade Powell, David H. Reitze, Yi-Ming Hu, Sweta Shah, K. Izumi, D. Passuello, Nicolas Leroy, M. Barsuglia, E. O. Lebigot, Vuk Mandic, Alberto Di Lieto, Ignacio Santiago-Prieto, G. Vedovato, W. Katzman, S. E. Dwyer, David Keitel, Richard Gustafson, Suvadeep Bose, Z. Márka, Tomasz Bulik, Alexander Ivanov, C. Affeldt, P. Thomas, Jean-Pierre Zendri, Trevor Sidery, H. Heitmann, Ryan DeRosa, V. Loriette, Francesco Salemi, Pierre-François Cohadon, V. Litvine, Gurumurthy Rajalakshmi, O. Bock, István Rácz, K. L. Dooley, Sabrina D'Antonio, Joshua Yablon, Warren Anderson, Eric K. Gustafson, Sina Koehlenbeck, Jocelyn Read, F. Carbognani, J. Logue, H. J. Bulten, S. Gossler, David Kinzel, Almir Alemic, P. J. Veitch, Amber Stuver, Sanichiro Yoshida, Badri Krishnan, T. P. Bodiya, C. Vorvick, Marc Normandin, Ettore Majorana, Gary McIntyre, M. Edwards, Peter Wessels, Rosa Poggiani, Erik Katsavounidis, Namjun Kim, François Bondu, P. Leaci, A. Colla, Sean Morriss, M. Factourovich, P. Astone, J. Betzwieser, V. Kondrashov, Lisa Barsotti, Bala R. Iyer, Kieran Craig, Shaun Hooper, Valeria Malvezzi, Warren W. Johnson, Jay Marx, Antoine Heidmann, Piotr Jaranowski, Florent Robinet, P. Raffai, Kyle Ryan, Mark Barbet, Samuel Franco, Eric Thrane, Eric W. James, Manasadevi Thirugnanasamba, Sarah Caudill, E. Goetz, Scott Koranda, T. t. Fricke, J. B. Kanner, A. R. Wade, Rainer Weiss, Xu Chen, G. Bergmann, L. Matone, T. Dayanga, Martin van Beuzekom, Les Wade, Irene Di Palma, Young-Min Kim, Albert Lazzarini, Anthony Kremin, Fausto Acernese, Rajesh Kumar, R. J. G. Jonker, H. Overmier, Robert M. S. Schofield, Jessica McIver, Sang Oh, G. Mazzolo, G. Kuehn, D. Barker, K. Wette, F. Ricci, N. Mazumder, R. Quitzow-James, R. Day, Vladimir B. Braginsky, Maik Frede, C. C. Yancey, Giacomo Ciani, A. Mullavey, John J. Oh, D. Sellers, Alastair Grant, N. Morgado, H. Vahlbruch, A. Cumming, C. M. Mow-Lowry, H. Fehrmann, J. Meidam, Lisa M. Goggin, K. Riles, F. Ohme, S. J. Chamberlin, Sergey P. Vyatchanin, Calum Torrie, J. Hanks, J. Y. Vinet, Archana Pai, E. J. King, Hyun Lee, B. P. Abbott, Andrea Moggi, Jean-Daniel Fournier, Rory Smith, Hernan Daveloza, D. Sigg, S. W. Ballmer, Edwin J. Son, D. Ugolini, S. Vass, F. Paoletti, P. Ruggi, J. Eichholz, M. J. Cowart, Keiko Kokeyama, Riccardo Sturani, Andrzej Królak, Laurent Pinard, Fumiko Kawazoe, Tristan Briant, Benjamin William Allen, Stefan Hild, Y. Ma, E. Genin, N. D. Smith-Lefebvre, Graham Woan, Stuart Reid, Steven D. Penn, Yuri Minenkov, Laura Cadonati, Mohana Mageswaran, Veronica Lockett, N. Letendre, Karsten Danzmann, C. Aulbert, R. Cavalieri, Scott Dossa, H. Wittel, Walter Del Pozzo, Riccardo DeSalvo, C. Messenger, Bastian Schulz, R. Vincent-Finley, Jeffery Kline, H. Radkins, J. D. Lough, S. T. Countryman, S. H. Huttner, Fabrice Matichard, W. Kells, Jacob Scheuer, M. Jacobson, M. Weinert, P. Campsie, Michelle E. Walker, J. Birch, Katrin Dahl, A. Libson, M. Punturo, D. Hoak, D. Sentenac, Patrick Brady, Leopoldo Milano, Slawomir Gras, F. Fidecaro, S. Biscans, Fred Raab, Valentina D. Mangano, P. Baker, M. Mantovani, Andrew Melatos, E. Saracco, A. Brillet, Gary Hemming, Michail Agathos, A. Masserot, Santiago Caride, C. L. Mueller, B. Behnke, Matthew Heintze, Richard L. Savage, Alberto Vecchio, G. M. Harry, E. Oelker, K. Venkateswara, Benjamin Aylott, Daniel Kozak, Martina Neri, A. S. Bell, John Miller, T. Prestegard, Charles Celerier, Craig Lawrie, Lee Samuel Finn, Fafhan Feroz, Soma Mukherjee, R. L. McCarthy, Yuri Levin, Thanh Vinh Nguyen, David Blair, Vincenzo Dattilo, E. Coccia, C. Graef, B. A. Weaver, Dmitry Simakov, M. Brinkmann, L. Prokhorov, Will M. Farr, Elisabetta Cesarini, Troy Williams, Neil Gordon, Patrice Hello, Nancy Aggarwal, Robert Stone, Jordan Camp, James S. Clark, M. J. Hart, Richard O'Shaughnessy, B. Barr, Malik Rakhmanov, A. Pasqualetti, Roman Schnabel, J. G. Rollins, F. Y. Khalili, F. Travasso, Michał Bejger, Timo Denker, Luke Williams, J. C. Driggers, L. Austin, A. M. Gretarsson, A. R. Williamson, D. Feldbaum, S. Verma, A. Mytidis, J. E. Brau, L. Martinelli, Susan M. Scott, F. Marion, Efim A. Khazanov, Michael Thomas, A. Effler, Xiaoge Wang, Irene Fiori, G. Ballardin, Moritz Mehmet, David Stops, David Coward, Li Ju, Oleg Palashov, Daniel A. Shaddock, Adam Mercer, A. Basti, Philipp Moesta, Michael Rodruck, A. Allocca, Vincent Dolique, G. Valdes, Walter Winkler, Huan Yang, A. Perreca, M. Drago, B. Hughey, B. J. J. Slagmolen, Sheon Chua, M. Phelps, C. J. Guido, Paul Hopkins, Chiara M. F. Mingarelli, A. S. Markosyan, J. Hanson, Robert Taylor, B. C. Stephens, Mátyás Vasúth, Koji Arai, P. G. 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Wang, APC - Cosmologie, AstroParticule et Cosmologie (APC (UMR_7164)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Observatoire de Paris, Université Paris sciences et lettres (PSL), Laboratoire de l'Accélérateur Linéaire (LAL), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Astrophysique Relativiste Théories Expériences Métrologie Instrumentation Signaux (ARTEMIS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Physique de Rennes (IPR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des matériaux avancés (LMA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Annecy de Physique des Particules (LAPP), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), APC - Gravitation (APC-Gravitation), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Max-Planck-Institut für Gravitationsphysik ( Albert-Einstein-Institut ) (AEI), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), IVC Lab, Lenovo Research, Lenovo, European Synchrotron Radiation Facility (ESRF), Physique Corpusculaire et Cosmologie - Collège de France ( PCC ), Collège de France ( CdF ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Collège de France ( CdF ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -AstroParticule et Cosmologie ( APC - UMR 7164 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Observatoire de Paris-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire de l'Accélérateur Linéaire ( LAL ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Astrophysique Relativiste Théories Expériences Métrologie Instrumentation Signaux ( ARTEMIS ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de la Côte d'Azur, Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Physique de Rennes ( IPR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des matériaux avancés ( LMA ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Annecy de Physique des Particules ( LAPP/Laboratoire d'Annecy-le-Vieux de Physique des Particules ), Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ), AstroParticule et Cosmologie ( APC - UMR 7164 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), APC - Gravitation ( APC-Gravitation ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Max-Planck-Institut für Gravitationsphysik (Albert-Einstein-Institut), Max-Planck-Institut-Max-Planck-Institut, ESPCI ParisTech, Universitá degli Studi dell’Insubria, European Synchrotron Radiation Facility ( ESRF ), Aasi, J., Abbott, B. P., Abbott, R., Abbott, T., Abernathy, M. R., Acernese, F., Ackley, K., Adams, C., Adams, T., Addesso, P., Adhikari, R. X., Affeldt, C., Agathos, M., Aggarwal, N., Aguiar, O. D., Ain, A., Ajith, P., Alemic, A., Allen, B., Allocca, A., Amariutei, D., Andersen, M., Anderson, R., Anderson, S. B., Anderson, W. G., Arai, K., Araya, M. C., Arceneaux, C., Areeda, J., Aston, S. M., Astone, P., Aufmuth, P., Aulbert, C., Austin, L., Aylott, B. E., Babak, S., Baker, P. T., Ballardin, G., Ballmer, S. W., Barayoga, J. C., Barbet, M., Barish, B. C., Barker, D., Barone, F., Barr, B., Barsotti, L., Barsuglia, M., Barton, M. A., Bartos, I., Bassiri, R., Basti, A., Batch, J. C., Bauchrowitz, J., Bauer, T. h. S., Bavigadda, V., Behnke, B., Bejger, M., Beker, M. G., Belczynski, C., Bell, A. S., Bell, C., Benacquista, M., Bergmann, G., Bersanetti, D., Bertolini, A., Betzwieser, J., Beyersdorf, P. T., Bilenko, I. A., Billingsley, G., Birch, J., Biscans, S., Bitossi, M., Bizouard, M. A., Black, E., Blackburn, J. K., Blackburn, L., Blair, D., Bloemen, S., Bock, O., Bodiya, T. P., Boer, M., Bogaert, G., Bogan, C., Bond, C., Bondu, F., Bonelli, L., Bonnand, R., Bork, R., Born, M., Boschi, V., Sukanta, Bose, Bosi, L., Bradaschia, C., Brady, P. R., Braginsky, V. B., Branchesi, M., Brau, J. E., Briant, T., Bridges, D. O., Brillet, A., Brinkmann, M., Brisson, V., Brooks, A. F., Brown, D. A., Brown, D. D., Brckner, F., Buchman, S., Bulik, T., Bulten, H. J., Buonanno, A., Burman, R., Buskulic, D., Buy, C., Cadonati, L., Cagnoli, G., Caldern Bustillo, J., Calloni, Enrico, Camp, J. B., Campsie, P., Cannon, K. C., Canuel, B., Cao, J., Capano, C. D., Carbognani, F., Carbone, L., Caride, S., Castiglia, A., Caudill, S., Cavagli, M., Cavalier, F., Cavalieri, R., Celerier, C., Cella, G., Cepeda, C., Cesarini, E., Chakraborty, R., Chalermsongsak, T., Chamberlin, S. J., Chao, S., Charlton, P., Chassande Mottin, E., Chen, X., Chen, Y., Chincarini, A., Chiummo, A., Cho, H. S., Chow, J., Christensen, N., Chu, Q., Chua, S. S. Y., Chung, S., Ciani, G., Clara, F., Clark, J. A., Cleva, F., Coccia, E., Cohadon, P. F., Colla, A., Collette, C., Colombini, M., Cominsky, L., Constancio, M., Conte, A., Cook, D., Corbitt, T. R., Cordier, M., Cornish, N., Corpuz, A., Corsi, A., Costa, C. A., Coughlin, M. W., Coughlin, S., Coulon, J. P., Countryman, S., Couvares, P., Coward, D. M., Cowart, M., Coyne, D. C., Coyne, R., Craig, K., Creighton, J. D. E., Crowder, S. G., Cumming, A., Cunningham, L., Cuoco, E., Dahl, K., Dal Canton, T., Damjanic, M., Danilishin, S. L., Dantonio, S., Danzmann, K., Dattilo, V., Daveloza, H., Davier, M., Davies, G. S., Daw, E. J., Day, R., Dayanga, T., Debreczeni, G., Degallaix, J., Delglise, S., Del Pozzo, W., Denker, T., Dent, T., Dereli, H., Dergachev, V., DE ROSA, Rosario, Derosa, R. T., Desalvo, R., Dhurandhar, S., Daz, M., Di Fiore, L., Di Lieto, A., Di Palma, I., Di Virgilio, A., Dolique, V., Donath, A., Donovan, F., Dooley, K. L., Doravari, S., Dossa, S., Douglas, R., Downes, T. P., Drago, M., Drever, R. W. P., Driggers, J. C., Du, Z., Ducrot, M., Dwyer, S., Eberle, T., Edo, T., Edwards, M., Effler, A., Eggenstein, H., Ehrens, P., Eichholz, J., Eikenberry, S. S., Endrczi, G., Essick, R., Etzel, T., Evans, M., Evans, T., Factourovich, M., Fafone, V., Fairhurst, S., Fang, Q., Farinon, S., Farr, B., Farr, W. M., Favata, M., Fehrmann, H., Fejer, M. M., Feldbaum, D., Feroz, F., Ferrante, I., Ferrini, F., Fidecaro, F., Finn, L. S., Fiori, I., Fisher, R. P., Flaminio, R., Fournier, J. D., Franco, S., Frasca, S., Frasconi, F., Frede, M., Frei, Z., Freise, A., Frey, R., Fricke, T. T., Fritschel, P., Frolov, V. V., Fulda, P., Fyffe, M., Gair, J., Gammaitoni, L., Gaonkar, S., Garufi, Fabio, Gehrels, N., Gemme, G., Gendre, B., Genin, E., Gennai, A., Ghosh, S., Giaime, J. A., Giardina, K. D., Giazotto, A., Gill, C., Gleason, J., Goetz, E., Goetz, R., Goggin, L. M., Gondan, L., Gonzlez, G., Gordon, N., Gorodetsky, M. L., Gossan, S., Goler, S., Gouaty, R., Grf, C., Graff, P. B., Granata, M., Grant, A., Gras, S., Gray, C., Greenhalgh, R. J. S., Gretarsson, A. M., Groot, P., Grote, H., Grover, K., Grunewald, S., Guidi, G. M., Guido, C., Gushwa, K., Gustafson, E. K., Gustafson, R., Hammer, D., Hammond, G., Hanke, M., Hanks, J., Hanna, C., Hanson, J., Harms, J., Harry, G. M., Harry, I. W., Harstad, E. D., Hart, M., Hartman, M. T., Haster, C. J., Haughian, K., Heidmann, A., Heintze, M., Heitmann, H., Hello, P., Hemming, G., Hendry, M., Heng, I. S., Heptonstall, A. W., Heurs, M., Hewitson, M., Hild, S., Hoak, D., Hodge, K. A., Holt, K., Hooper, S., Hopkins, P., Hosken, D. J., Hough, J., Howell, E. J., Hu, Y., Huerta, E., Hughey, B., Husa, S., Huttner, S. H., Huynh, M., Huynh Dinh, T., Ingram, D. R., Inta, R., Isogai, T., Ivanov, A., Iyer, B. R., Izumi, K., Jacobson, M., James, E., Jang, H., Jaranowski, P., Ji, Y., Jimnez Forteza, F., Johnson, W. W., Jones, D. I., Jones, R., Jonker, R. J. G., Ju, L., Haris, K, Kalmus, P., Kalogera, V., Kandhasamy, S., Kang, G., Kanner, J. B., Karlen, J., Kasprzack, M., Katsavounidis, E., Katzman, W., Kaufer, H., Kawabe, K., Kawazoe, F., Kflian, F., Keiser, G. M., Keitel, D., Kelley, D. B., Kells, W., Khalaidovski, A., Khalili, F. Y., Khazanov, E. A., Kim, C., Kim, K., Kim, N., Kim, N. G., Kim, Y. M., King, E. J., King, P. J., Kinzel, D. L., Kissel, J. S., Klimenko, S., Kline, J., Koehlenbeck, S., Kokeyama, K., Kondrashov, V., Koranda, S., Korth, W. Z., Kowalska, I., Kozak, D. B., Kremin, A., Kringel, V., Krishnan, B., Krlak, A., Kuehn, G., Kumar, A., Nanda Kumar, D., Kumar, P., Kumar, R., Kuo, L., Kutynia, A., Kwee, P., Landry, M., Lantz, B., Larson, S., Lasky, P. D., Lawrie, C., Lazzarini, A., Lazzaro, C., Leaci, P., Leavey, S., Lebigot, E. O., Lee, C. H., Lee, H. K., Lee, H. M., Lee, J., Leonardi, M., Leong, J. R., Le Roux, A., Leroy, N., Letendre, N., Levin, Y., Levine, B., Lewis, J., T. G. F., Li, Libbrecht, K., Libson, A., Lin, A. 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Subjects
SPACE-TELESCOPE EVIDENCE, Physics and Astronomy (miscellaneous), Astronomy, Pacs number: 04.70.-s, Astrophysics, 01 natural sciences, Pacs number: 04.80.Nn, General Relativity and Quantum Cosmology, Gravitation, GLOBULAR-CLUSTER M15, Gravitational waves, black holes, interferometer, CORE, Quantum Cosmology, gravitational wave, 010303 astronomy & astrophysics, EQUATIONS, QC, QB, Physics, Pacs number: 07.05.Kf, Oscillation, Settore FIS/01 - Fisica Sperimentale, CANDIDATE, Nuclear and High Energy Physics, PERTURBATIONS, Pacs number: 95.85.Sz, [PHYS.GRQC]Physics [physics]/General Relativity and Quantum Cosmology [gr-qc], Gravitational wave, General Relativity, Stellar mass, General relativity, MERGERS, Astrophysics::High Energy Astrophysical Phenomena, FOS: Physical sciences, General Relativity and Quantum Cosmology (gr-qc), Astrophysics::Cosmology and Extragalactic Astrophysics, [ PHYS.GRQC ] Physics [physics]/General Relativity and Quantum Cosmology [gr-qc], Settore FIS/05 - Astronomia e Astrofisica, 0103 physical sciences, FIELD, COLLAPSE, Astrophysics::Galaxy Astrophysics, 010308 nuclear & particles physics, BINARY, Mass ratio, LIGO, 13. Climate action, Globular cluster, [PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph]
Abstract

We report results from a search for gravitational waves produced by perturbed intermediate mass black holes (IMBH) in data collected by LIGO and Virgo between 2005 and 2010. The search was sensitive to astrophysical sources that produced damped sinusoid gravitational wave signals, also known as ringdowns, with frequency $50\le f_{0}/\mathrm{Hz} \le 2000$ and decay timescale $0.0001\lesssim \tau/\mathrm{s} \lesssim 0.1$ characteristic of those produced in mergers of IMBH pairs. No significant gravitational wave candidate was detected. We report upper limits on the astrophysical coalescence rates of IMBHs with total binary mass $50 \le M/\mathrm{M}_\odot \le 450$ and component mass ratios of either 1:1 or 4:1. For systems with total mass $100 \le M/\mathrm{M}_\odot \le 150$, we report a 90%-confidence upper limit on the rate of binary IMBH mergers with non-spinning and equal mass components of $6.9\times10^{-8}\,$Mpc$^{-3}$yr$^{-1}$. We also report a rate upper limit for ringdown waveforms from perturbed IMBHs, radiating 1% of their mass as gravitational waves in the fundamental, $\ell=m=2$, oscillation mode, that is nearly three orders of magnitude more stringent than previous results., Comment: for the science summary, see http://www.ligo.org/science/Publication-S5S6RD/index.php

Published
2014

29. Characterization of Within-Host Plasmodium falciparum Diversity Using Next-Generation Sequence Data

Author

Ogobara K. Doumbo, Daniel Alcock, Jean-Bosco Ouédraogo, Gareth Maslen, Bronwyn MacInnis, Dominic P. Kwiatkowski, Valentina D. Mangano, Sarah Auburn, Susana Campino, Taane G. Clark, Kirk A. Rockett, Magnus Manske, Abdoulaye Djimde, Olivo Miotto, and Issaka Zongo

Subjects
PARASITES, Epidemiology, Population Dynamics, lcsh:Medicine, Genome-wide association study, CHILDREN, Protozoology, Mali, Polymerase Chain Reaction, 0302 clinical medicine, Multiplicity of infection, MALARIA INFECTIONS, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Genomics, Biodiversity, GENOME, Infectious Diseases, Medicine, GENETICALLY DIVERSE, Research Article, Genotype, SURFACE, Plasmodium falciparum, 030231 tropical medicine, Antigens, Protozoan, Locus (genetics), Computational biology, Biology, Microbiology, Polymorphism, Single Nucleotide, DNA sequencing, 03 medical and health sciences, CLINICAL MALARIA, Burkina Faso, Genetic variation, Animals, Humans, Genetic variability, DRUG-TREATMENT, EVOLUTION, VIRULENCE, Genotyping, Alleles, 030304 developmental biology, Models, Statistical, Population Biology, Models, Genetic, lcsh:R, Tropical Diseases (Non-Neglected), Genetic Variation, Sequence Analysis, DNA, Genetic divergence, Parastic Protozoans, lcsh:Q, Genome-Wide Association Study
Abstract

Our understanding of the composition of multi-clonal malarial infections and the epidemiological factors which shape their diversity remain poorly understood. Traditionally within-host diversity has been defined in terms of the multiplicity of infection (MOI) derived by PCR-based genotyping. Massively parallel, single molecule sequencing technologies now enable individual read counts to be derived on genome-wide datasets facilitating the development of new statistical approaches to describe within-host diversity. In this class of measures the F(WS) metric characterizes within-host diversity and its relationship to population level diversity. Utilizing P. falciparum field isolates from patients in West Africa we here explore the relationship between the traditional MOI and F(WS) approaches. F(WS) statistics were derived from read count data at 86,158 SNPs in 64 samples sequenced on the Illumina GA platform. MOI estimates were derived by PCR at the msp-1 and -2 loci. Significant correlations were observed between the two measures, particularly with the msp-1 locus (P = 5.92×10(-5)). The F(WS) metric should be more robust than the PCR-based approach owing to reduced sensitivity to potential locus-specific artifacts. Furthermore the F(WS) metric captures information on a range of parameters which influence out-crossing risk including the number of clones (MOI), their relative proportions and genetic divergence. This approach should provide novel insights into the factors which correlate with, and shape within-host diversity.

Published
2012

30. Wide cross-reactivity between Anopheles gambiae and Anopheles funestus SG6 salivary proteins supports exploitation of gSG6 as a marker of human exposure to major malaria vectors in tropical Africa

Author

Sodiomon B. Sirima, Vincenzo Petrarca, David Modiano, Cinzia Rizzo, Gabriella Fiorentino, Raffaele Ronca, Valentina D. Mangano, Bruno Arcà, Issa Nebie, Rizzo, C., Ronca, R., Fiorentino, Gabriella, Mangano, V. D., Sirima, S. B., Nèbiè, I., Petrarca, V., Modiano, D., and Arcà, B.

Subjects
Anopheles gambiae, Disease Vectors, medicine.disease_cause, Cross-reactivity, immune response, 0302 clinical medicine, Child, salivary antigen, 0303 health sciences, education.field_of_study, biology, Immunogenicity, Middle Aged, 3. Good health, Infectious Diseases, Child, Preschool, Insect Proteins, Female, epidemiology, Anophele, Adult, anopheles gambiae, medicine.medical_specialty, lcsh:Arctic medicine. Tropical medicine, Adolescent, malaria epidemiology, lcsh:RC955-962, 030231 tropical medicine, Population, malaria, Zoology, Cross Reactions, lcsh:Infectious and parasitic diseases, Young Adult, 03 medical and health sciences, Anopheles, Burkina Faso, parasitic diseases, medicine, Animals, Humans, lcsh:RC109-216, salivary antigens, Salivary Proteins and Peptides, education, Anopheles stephensi, 030304 developmental biology, Research, Infant, biology.organism_classification, medicine.disease, Virology, Parasitology, Immunoglobulin G, Tropical medicine, Malaria
Abstract

Background The Anopheles gambiae gSG6 is an anopheline-specific salivary protein which helps female mosquitoes to efficiently feed on blood. Besides its role in haematophagy, gSG6 is immunogenic and elicits in exposed individuals an IgG response, which may be used as indicator of exposure to the main African malaria vector A. gambiae. However, malaria transmission in tropical Africa is sustained by three main vectors (A. gambiae, Anopheles arabiensis and Anopheles funestus) and a general marker, reflecting exposure to at least these three species, would be especially valuable. The SG6 protein is highly conserved within the A. gambiae species complex whereas the A. funestus homologue, fSG6, is more divergent (80% identity with gSG6). The aim of this study was to evaluate cross-reactivity of human sera to gSG6 and fSG6. Methods The A. funestus SG6 protein was expressed/purified and the humoral response to gSG6, fSG6 and a combination of the two antigens was compared in a population from a malaria hyperendemic area of Burkina Faso where both vectors were present, although with a large A. gambiae prevalence (>75%). Sera collected at the beginning and at the end of the high transmission/rainy season, as well as during the following low transmission/dry season, were analysed. Results According to previous observations, both anti-SG6 IgG level and prevalence decreased during the low transmission/dry season and showed a typical age-dependent pattern. No significant difference in the response to the two antigens was found, although their combined use yielded in most cases higher IgG level. Conclusions Comparative analysis of gSG6 and fSG6 immunogenicity to humans suggests the occurrence of a wide cross-reactivity, even though the two proteins carry species-specific epitopes. This study supports the use of gSG6 as reliable indicator of exposure to the three main African malaria vectors, a marker which may be useful to monitor malaria transmission and evaluate vector control measures, especially in conditions of low malaria transmission and/or reduced vector density. The Anopheles stephensi SG6 protein also shares 80% identity with gSG6, suggesting the attractive possibility that the A. gambiae protein may also be useful to assess human exposure to several Asian malaria vectors.

Published
2011

31. Humoral response to the Anopheles gambiae salivary protein gSG6 : a serological indicator of exposure to afrotropical malaria vectors

Author

Vincenzo Petrarca, David Modiano, Fabrizio Lombardo, Federica Verra, Sodiomon B. Sirima, Raffaele Ronca, Gabriella Fiorentino, Issa Nebie, Bruno Arcà, Anne Poinsignon, Valentina D. Mangano, Franck Remoue, Mario Coluzzi, Cinzia Rizzo, Transmission-Interactions-Adaptations hôtes/vecteurs/pathogènes (MIVEGEC-TRIAD), Evolution des Systèmes Vectoriels (ESV), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Rizzo, C., Ronca, R., Fiorentino, Gabriella, Verra, F., Mangano, V., Poinsignon, A., Sirima, S. B., Nébié, I., Lombardo, F., Remoue, F., Coluzzi, M., Petrarca, V., Modiano, D., and Arcà, B.

Subjects
Saliva, Aging, Plasmodium, Anatomy and Physiology, salivary antigen, Epidemiology, medicine.medical_treatment, Anopheles gambiae, Immunoglobulin G, Serology, Immune tolerance, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immune Physiology, Ethnicity, Prevalence, Immune Response, ComputingMilieux_MISCELLANEOUS, Desensitization (medicine), 2. Zero hunger, 0303 health sciences, Multidisciplinary, biology, 3. Good health, Infectious Diseases, Medicine, Insect Proteins, Seasons, Anophele, Research Article, anopheles gambiae, malaria epidemiology, Science, 030231 tropical medicine, Immunology, Immunoglobulins, Microbiology, Vector Biology, Antibodies, 03 medical and health sciences, Antigen, Anopheles, Burkina Faso, parasitic diseases, medicine, Immune Tolerance, Parasitic Diseases, Animals, Humans, salivary antigens, Salivary Proteins and Peptides, Biology, 030304 developmental biology, Tropical Climate, Immunity, Vectors and Hosts, medicine.disease, biology.organism_classification, Virology, humoral immune response, Malaria, Immunity, Humoral, Insect Vectors, Biomarker Epidemiology, Case-Control Studies, Humoral Immunity, biology.protein, Parasitology, Clinical Immunology
Abstract

Salivary proteins injected by blood feeding arthropods into their hosts evoke a saliva-specific humoral response which can be useful to evaluate exposure to bites of disease vectors. However, saliva of hematophagous arthropods is a complex cocktail of bioactive factors and its use in immunoassays can be misleading because of potential cross-reactivity to other antigens. Toward the development of a serological marker of exposure to Afrotropical malaria vectors we expressed the Anopheles gambiae gSG6, a small anopheline-specific salivary protein, and we measured the anti-gSG6 IgG response in individuals from a malaria hyperendemic area of Burkina Faso, West Africa. The gSG6 protein was immunogenic and anti-gSG6 IgG levels and/or prevalence increased in exposed individuals during the malaria transmission/rainy season. Moreover, this response dropped during the intervening low transmission/dry season, suggesting it is sensitive enough to detect variation in vector density. Members of the Fulani ethnic group showed higher anti-gSG6 IgG response as compared to Mossi, a result consistent with the stronger immune reactivity reported in this group. Remarkably, anti-gSG6 IgG levels among responders were high in children and gradually declined with age. This unusual pattern, opposite to the one observed with Plasmodium antigens, is compatible with a progressive desensitization to mosquito saliva and may be linked to the continued exposure to bites of anopheline mosquitoes. Overall, the humoral anti-gSG6 IgG response appears a reliable serological indicator of exposure to bites of the main African malaria vectors (An. gambiae, Anopheles arabiensis and, possibly, Anopheles funestus) and it may be exploited for malaria epidemiological studies, development of risk maps and evaluation of anti-vector measures. In addition, the gSG6 protein may represent a powerful model system to get a deeper understanding of molecular and cellular mechanisms underlying the immune tolerance and progressive desensitization to insect salivary allergens.

Published
2011

32. Population genetic analysis of Plasmodium falciparum parasites using a customized Illumina GoldenGate genotyping assay

Author

Abdoulaye Djimde, Peter Siba, Hongying Jiang, Xin-zhuan Su, Steven M. Kiara, Duong Socheat, Bronwyn MacInnis, Kirk A. Rockett, Alexis Nzila, Nicholas J. White, François Nosten, Chris I. Newbold, Issaka Zongo, Ogobara K. Doumbo, Chanaki Amaratunga, Kevin Marsh, Katja Kivinen, Susana Campino, Rick M. Fairhurst, Jean-Bosco Ouédraogo, Taane G. Clark, Rhian Gwilliam, Steffen Borrmann, Panos Deloukas, Valentina D. Mangano, Sarah Auburn, Mallika Imwong, Dominic P. Kwiatkowski, Tim J. Anderson, Pascal Michon, and Ivo Mueller

Subjects
Time Factors, DIVERSITY, lcsh:Medicine, Protozoology, 0302 clinical medicine, Genotype, Malaria, Falciparum, lcsh:Science, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, High-Throughput Nucleotide Sequencing, 3. Good health, GENOME, PCR, Infectious Diseases, Microsatellite, Medicine, MULTIPLE DISPLACEMENT AMPLIFICATION, Research Article, Cloning, Organism, MICROSATELLITE, 030231 tropical medicine, Population, Plasmodium falciparum, SEQUENCE, Polymorphism, Single Nucleotide, Microbiology, 03 medical and health sciences, Culture Techniques, parasitic diseases, Parasitic Diseases, Genetic variability, education, Genotyping, Biology, ANTIMALARIAL-DRUG RESISTANCE, 030304 developmental biology, Genetic diversity, IDENTIFICATION, Population Biology, lcsh:R, MALARIA, Multiple displacement amplification, Computational Biology, Tropical Diseases (Non-Neglected), DNA, Protozoan, biology.organism_classification, Malaria, Genetic Loci, Genetic Polymorphism, Parastic Protozoans, lcsh:Q, Laboratories, Population Genetics
Abstract

The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum.

Published
2010

33. HLA-DRB1 and -DQB1 loci in three west African ethnic groups: Genetic relationship with sub-Saharan African and European populations

Author

Gaia Luoni, Issa Nebie, Valentina D. Mangano, P Lulli, B S Sirima, Chiara Batini, Vincenzo Petrarca, David Modiano, Luciana Chessa, and Annamaria Onori

Subjects
Adult, Adolescent, Immunology, Population, Ethnic group, Autoimmunity, Biology, Young Adult, HLA-DQ Antigens, parasitic diseases, West Africa, medicine, Immunology and Allergy, HLA-DQ beta-Chains, Humans, Allele, education, Child, HLA-DRB1, Africa South of the Sahara, Aged, education.field_of_study, Membrane Glycoproteins, Haplotype, General Medicine, HLA-DR Antigens, Middle Aged, medicine.disease, Malaria, Europe, HLA, Africa, Western, Genetics, Population, Genetic distance, Sympatric speciation, Genetic Loci, west Africa, Demography, HLA-DRB1 Chains
Abstract

7 páginas, 3 figuras, 4 tablas.-- et al., The Fulani of west Africa have been shown to be less susceptible to malaria and to mount a stronger immune response to malaria than sympatric ethnic groups. The analysis of HLA diversity is useful for the assessment of the genetic distance between the Fulani and sympatric populations, which represents the necessary theoretical background for the investigation of genetic determinants of susceptibility to malaria. We assessed the polymorphism of HLA-DRB1 and -DQB1 loci and analyzed the distribution of alleles/haplotypes in Fulani, Mossi, and Rimaibé from Burkina Faso. We then investigated the genetic relationship of these three ethnic groups with other sub-Saharan African populations as well as with Europeans. We confirmed that the Fulani from Burkina Faso are genetically distinct from sympatric Mossi and Rimaibé. Furthermore the Fulani from Burkina Faso are close to those from The Gambia and, intriguingly, share the distribution of specific alleles with east African populations (Amhara and Oromo). It is noteworthy that the HLA-DRB1*04 and -DQB1*02 alleles, which are implicated in the development of several autoimmune diseases, are present at high frequency in the Fulani, suggesting their potential involvement in the enhanced immune reactivity observed in this population., This work is part of the activities of the BioMalPar European Network of Excellence supported by a European grant (LSHP-CT- 2004-503578) from the Priority 1 “Life Sciences, Genomics and Biotechnology for Health” in the 6th Framework Programme, and V.D.M. was funded by a BioMalPar PhD Fellowship. This work was further supported by grants from Italian Ministry of Education (COFIN, MIUR-PRIN 2006062857) and Istituto Pasteur–Fondazione Cenci Bolognetti, Sapienza Universitá di Roma.

Published
2009

34. The genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome wide association studies

Author

David Modiano, Federica Verra, and Valentina D. Mangano

Subjects
Erythrocytes, Immunology, Plasmodium falciparum, malaria, Genome-wide association study, Genome, polymorphism, Genetic variation, medicine, Animals, Humans, Genetic Predisposition to Disease, genetics, Malaria, Falciparum, acquired immunity, immunoepidemiology, Genetic association, Genetics, Polymorphism, Genetic, biology, Genome, Human, Immunity, Proteins, biology.organism_classification, medicine.disease, Genetic epidemiology, Parasitology, Human genome, Malaria, Genome-Wide Association Study
Abstract

Plasmodium falciparum represents one of the strongest selective forces on the human genome. This stable and perennial pressure has contributed to the progressive accumulation in the exposed populations of genetic adaptations to malaria. Descriptive genetic epidemiology provides the initial step of a logical procedure of consequential phases spanning from the identification of genes involved in the resistance/susceptibility to diseases, to the determination of the underlying mechanisms and finally to the possible translation of the acquired knowledge in new control tools. In malaria, the rational development of this strategy is traditionally based on complementary interactions of heterogeneous disciplines going from epidemiology to vaccinology passing through genetics, pathogenesis and immunology. New tools including expression profile analysis and genome-wide association studies are recently available to explore the complex interactions of host-parasite co-evolution. Particularly, the combination of genome-wide association studies with large multi-centre initiatives can overcome the limits of previous results due to local population dynamics. Thus, we anticipate substantial advances in the interpretation and validation of the effects of genetic variation on malaria susceptibility, and thereby on molecular mechanisms of protective immune responses and pathogenesis.

Published
2009

35. A global network for investigating the genomic epidemiology of malaria

Author

Julie Makani, Kathryn Fitzpatrick, Ogobara K. Duombo, Jennifer Evans, Claire Potter, Giorgio Sirugo, Enmoore Lin, Christina Hubbart, Abier Elzein, Martha M. Lemnge, Anthony Enimil, Alioune Ly, Olukemi K. Amodu, Valentina D. Mangano, Angie Green, Alphaxard Manjurano, Dominic P. Kwiatkowski, Ivo Mueller, David Barnwell, Anna E. Jeffreys, Marryat Stevens, Thomas N. Williams, David Modiano, Sarah J. Dunstan, Taane G. Clark, Susana Campino, Tobias O. Apinjoh, Tran Tinh Hien, Sodiomon B. Sirima, David J. Conway, Terrie Taylor, Anavaj Sakuntabhai, L. Amenga-Etego, Catherine L. Moyes, Nguyen Ngoc Quyen, Laurens Manning, Mahamadou Diakite, Katharine Cook, Patrick H. Corran, Jeremy Farrar, Nadira D. Karunaweera, Kevin Marsh, Ogobara K. Doumbo, Catherine Hughes, Eric A. Achidi, Kirk A. Rockett, Chris Drakeley, Tsiri Agbenyega, Panos Deloukas, Mahamadou A. Thera, Kalifa Bojang, Julie Evans, Aaron Vanderwal, Christopher V. Plowe, Pascal Michon, Adama Tall, Aceme Nyika, Michael Gottlieb, Renee Watson, Gilbert Kokwaro, Jiannis Ragoussis, Eleanor M. Riley, Stephen Allen, Katja Kivinen, Muntaser E. Ibrahim, Bronwyn MacInnis, Vysaul Nyirongo, Elilan Somaskantharajah, Ayman S. Hussein, Alan Doyle, Carolyne M. Ndila, Michael T. Wilson, Muminatou Jallow, Jane Rogers, Abdoulaye Djimde, Deepika Fernando, Jantina DeVries, Patrick E. Duffy, Odile Puijalon, Yik Ying Teo, Kate Rowlands, Michael W. Parker, Deus S. Ishengoma, Marilyn McCreight, Edith C. Bougouma, Tom Oluoch, Rebecca Wrigley, Kerrin S. Small, Hugh Reyburn, Gareth Maslen, Malcolm E. Molyneux, Sarah Auburn, Eliza Hilton, Lee Hart, Pratap Singhasivanon, Alieu Mendy, Miguel A. Sanjoaquin, Magnus Manske, Anita Ghansah, Rajika L. Dewasurendra, Amagana Dolo, Dan Carucci, Theonest K. Mutabingwa, Prapat Suriyaphol, Marita Troye-Blomberg, Paul Risley, Susan Bull, Rolf D. Horstmann, Daniel Alcock, Ousman Toure, Kojo Koram, John C. Reeder, and Norbert Peshu

Subjects
Burden of disease, Economic growth, medicine.medical_specialty, Plasmodium, Population, Developing country, Global Health, Polymorphism, Single Nucleotide, Article, Political science, Epidemiology, Global network, Anopheles, Global health, medicine, Animals, Humans, education, education.field_of_study, Multidisciplinary, biology, business.industry, Genome, Human, biology.organism_classification, medicine.disease, Immunity, Innate, Biotechnology, Malaria, Epidemiologic Research Design, business, Genome-Wide Association Study
Abstract

Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries. © 2008 Macmillan Publishers Limited. All rights reserved.

Published
2008

36. Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations

Author

Valentina D. Mangano, Kirk A. Rockett, Andrew E. Fry, Susana Campino, Bert Mohr, Claire Vandiedonck, Dominic P. Kwiatkowski, Srilakshmi M. Raj, Julian Forton, Taane G. Clark, Sarah Auburn, and Anna Richardson

Subjects
lcsh:Medicine, Genomics, Biology, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Genetic variation, Humans, Allele, International HapMap Project, lcsh:Science, Gene, Alleles, 030304 developmental biology, Genetics, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Genome, Human, Genetics and Genomics/Functional Genomics, lcsh:R, Chromosome Mapping, Genetic Variation, Genetics and Genomics/Gene Expression, Genetics and Genomics/Gene Function, Gene Expression Regulation, Haplotypes, Human genome, lcsh:Q, 030217 neurology & neurosurgery, Research Article
Abstract

BACKGROUND: Localising regulatory variants that control gene expression is a challenge for genome research. Several studies have recently identified non-coding polymorphisms associated with inter-individual differences in gene expression. These approaches rely on the identification of signals of association against a background of variation due to other genetic and environmental factors. A complementary approach is to use an Allele-Specific Expression (ASE) assay, which is more robust to the effects of environmental variation and trans-acting genetic factors. METHODOLOGY/PRINCIPAL FINDINGS: Here we apply an ASE method which utilises heterozygosity within an individual to compare expression of the two alleles of a gene in a single cell. We used individuals from three HapMap population groups and analysed the allelic expression of genes with cis-regulatory regions previously identified using total gene expression studies. We were able to replicate the results in five of the six genes tested, and refined the cis- associated regions to a small number of variants. We also showed that by using multi-populations it is possible to refine the associated cis-effect DNA regions. CONCLUSIONS/SIGNIFICANCE: We discuss the efficacy and drawbacks of both total gene expression and ASE approaches in the discovery of cis-acting variants. We show that the ASE approach has significant advantages as it is a cleaner representation of cis-acting effects. We also discuss the implication of using different populations to map cis-acting regions and the importance of finding regulatory variants which contribute to human phenotypic variation.

Published
2008

37. Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria

Author

Veronica Santarlasci, Valentina D. Mangano, Federico Cozzolino, Germana Bancone, Enrico Maggi, Sergio Romagnani, Anna Rosa Sannella, Maria Lucibello, B S Sirima, Paolo Bonini, Enrico Garaci, Issa Nebie, AnnMaria Clemente, Francesco Annunziato, Lorenzo Cosmi, David Modiano, Federica Verra, Carlo Severini, Maria Torcia, Roberta Angeli, Francesco Liotta, Mario Coluzzi, Laura Maggi, and Francesca Frosali

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, Plasmodium falciparum, Population, Biology, Mali, T-Lymphocytes, Regulatory, Peripheral blood mononuclear cell, Immune system, Antigen, Burkina Faso, parasitic diseases, Ethnicity, medicine, Animals, Humans, Genetic Predisposition to Disease, IL-2 receptor, Malaria, Falciparum, education, Cell Proliferation, education.field_of_study, Multidisciplinary, Interleukin-2 Receptor alpha Subunit, FOXP3, Biological Sciences, Middle Aged, biology.organism_classification, medicine.disease, Immune System, Immunology, Leukocytes, Mononuclear, Female, Malaria
Abstract

Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNγ, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4 + CD25 + (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFβ, TGFβRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFβ and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25 + regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.

Published
2008

39. Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations.

Author

Valentina D Mangano, Taane G Clark, Sarah Auburn, Susana Campino, Mahamadou Diakite, Andrew E Fry, Angela Green, Anna Richardson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Michael J Griffiths, Charles Newton, Norbert Peshu, Thomas N Williams, Kevin Marsh, Malcolm E Molyneux, Terrie E Taylor, David Modiano, Dominic P Kwiatkowski, and Kirk A Rockett

Subjects
Medicine, Science
Abstract

Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.

Published
2009
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40. Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations.

Author

Susana Campino, Julian Forton, Srilakshmi Raj, Bert Mohr, Sarah Auburn, Andrew Fry, Valentina D Mangano, Claire Vandiedonck, Anna Richardson, Kirk Rockett, Taane G Clark, and Dominic P Kwiatkowski

Subjects
Medicine, Science
Abstract

BACKGROUND:Localising regulatory variants that control gene expression is a challenge for genome research. Several studies have recently identified non-coding polymorphisms associated with inter-individual differences in gene expression. These approaches rely on the identification of signals of association against a background of variation due to other genetic and environmental factors. A complementary approach is to use an Allele-Specific Expression (ASE) assay, which is more robust to the effects of environmental variation and trans-acting genetic factors. METHODOLOGY/PRINCIPAL FINDINGS:Here we apply an ASE method which utilises heterozygosity within an individual to compare expression of the two alleles of a gene in a single cell. We used individuals from three HapMap population groups and analysed the allelic expression of genes with cis-regulatory regions previously identified using total gene expression studies. We were able to replicate the results in five of the six genes tested, and refined the cis- associated regions to a small number of variants. We also showed that by using multi-populations it is possible to refine the associated cis-effect DNA regions. CONCLUSIONS/SIGNIFICANCE:We discuss the efficacy and drawbacks of both total gene expression and ASE approaches in the discovery of cis-acting variants. We show that the ASE approach has significant advantages as it is a cleaner representation of cis-acting effects. We also discuss the implication of using different populations to map cis-acting regions and the importance of finding regulatory variants which contribute to human phenotypic variation.

Published
2008
Full Text
View/download PDF

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