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Malaria remains one of the most significant health issues worldwide, accounting for 2.6% of the total global disease burden, and efforts to eliminate this threat continue. The key focus is to develop an efficient and long-term immunity to this disease via vaccination or therapeutic approach, and innovative strategies would enable us to achieve this target. Previously, using a mouse co-infection disease model, cross-protection was illustrated between Babesia microti and Plasmodium chabaudi. Hence, this study was planned to elucidate the impact of acute B. microti Peabody mjr and Plasmodium berghei ANKA co-infection on the consequence of complicated malaria in the C57BL/6J mouse model of malaria. Furthermore, immune response and pathological features were analyzed, and the course of the disease was compared among experimental groups. Our study established that acute B. microti infection activated immunity which was otherwise suppressed by P. berghei. The immunosuppressive tissue microenvironment was counteracted as evidenced by the enhanced immune cell population in co-infected mice, in contrast to P. berghei-infected control mice. Parasite sequestration in the brain, liver, lung, and spleen of co-infected mice was significantly decreased and tissue injury was ameliorated. Meanwhile, the serum levels of IFN-γ, TNF-α, and IL-12p70 were reduced while the secretion of IL-10 was promoted in co-infected mice. Eventually, co-infected mice showed an extended rate of survival. Hereby, the principal cytokines associated with the severity of malaria by P. berghei infection were TNF-α, IFN-γ, and IL-12p70. Moreover, it was evident from our flow cytometry results that innate immunity is crucial and macrophages are at the frontline of immunity against P. berghei infection. Our study recommended further investigations to shed light on the effects of babesiosis in suppressing malaria with the goal of developing Babesia-based therapy against malaria.

IntroductionThe protozoan parasite Babesia microti is the primary cause of human babesiosis. This parasite invades and multiplies inside red blood cells (RBCs), and infections differ significantly based on the age and immune competency of the host. The aim of this study was to investigate the use of serum metabolic profiling to identify systemic metabolic variations between B. microti-infected mice and noninfected controls.MethodsA serum metabolomics analysis of BALB/c mice that had been intraperitoneally injected with 107B. microti-infected RBCs was performed. Serum samples from the early infected group (2 days postinfection), the acutely infected group (9 days postinfection), and the noninfected group were collected and evaluated using a liquid chromatography−mass spectrometry (LC−MS) platform. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) identified metabolomic profiles that differentiated the B. microti-infected and noninfected groups.ResultsOur results confirm that the serum metabolome is significantly influenced by acute B. microti infection and show that infection results in dysregulation of metabolic pathways and perturbation of metabolites. Acutely infected mice displayed perturbations in metabolites associated with taurine and hypotaurine metabolism, histidine metabolism, and arachidonic acid metabolism. Taurocholic acid, anserine, and arachidonic acid may be potential candidates as serological biomarkers for diagnosing B. microti infection at the acute stage. These metabolites could be further examined for their role in disease complexity.DiscussionOur findings demonstrate that the acute stage of B. microti infection induces abnormalities in the metabolites present in mouse serum and provide new insight into the mechanisms involved in systemic metabolic changes that occur during B. microti infection.

IntroductionMalaria and Babesiosis are acute zoonotic disease that caused by infection with the parasite in the phylum Apicomplexa. Severe anemia and thrombocytopenia are the most common hematological complication of malaria and babesiosis. However, the mechanisms involved have not been elucidated, and only a few researches focus on the possible role of anti-erythrocyte and anti-platelet antibodies.MethodsIn this study, the Plasmodium yoelii, P. chabaudi, Babesia microti and B. rodhaini infected SCID and ICR mice. The parasitemia, survival rate, platelet count, anti-platelet antibodies, and the level of IFN-γ and interleukin (IL) -10 was tested after infection. Furthermore, the P. yoelii, P. chabaudi, B. rodhaini and B. microti infected ICR mice were treated with artesunate and diminaze, the development of the anti-erythrocyte and anti-platelet antibodies in chronic stage were examined. At last, the murine red blood cell and platelet membrane proteins probed with auto-antibodies induced by P. yoelii, P. chabaudi, B. rodhaini, and B. microti infection were characterized by proteomic analysis.Results and discussionThe high anti-platelet and anti-erythrocyte antibodies were detected in ICR mice after P. yoelii, P. chabaudi, B. rodhaini, and B. microti infection. Actin of murine erythrocyte and platelet is a common auto-antigen in Plasmodium and Babesia spp. infected mice. Our findings indicate that anti-erythrocyte and anti-platelet autoantibodies contribute to thrombocytopenia and anemia associated with Plasmodium spp. and Babesia spp. infection. This study will help to understand the mechanisms of malaria and babesiosis-related thrombocytopenia and hemolytic anemia.

Human babesiosis is a global emerging tick-borne disease caused by infection with intra-erythrocytic parasites of the genus Babesia. With the rise in human babesiosis cases, the discovery and development of new anti-Babesia drugs are essential. Phosphatidylinositol 4-kinase (PI4K) is a widely present eukaryotic enzyme that phosphorylates lipids to regulate intracellular signaling and trafficking. Previously, we have shown that MMV390048, an inhibitor of PI4K, showed potent inhibition against Babesia species, revealing PI4K as a druggable target for babesiosis. However, twice-administered, 7-day regimens failed to clear Babesia microti parasites from the immunocompromised host. Hence, in this study, we wanted to clarify whether targeting PI4K has the potential for the radical cure of babesiosis. In a B. microti-infected SCID mouse model, a 64-day-consecutive treatment with MMV390048 resulted in the clearance of parasites. Meanwhile, an atovaquone (ATO) resistant parasite line was isolated from the group treated with ATO plus azithromycin. A nonsynonymous variant in the Y272C of the cytochrome b gene was confirmed by sequencing. Likewise, MMV390048 showed potent inhibition against ATO-resistant parasites. These results provide evidence of PI4K as a viable drug target for the radical cure of babesiosis, which will contribute to designing new compounds that can eradicate parasites.

Babesiosis causes high morbidity and mortality in immunocompromised individuals. An earlier study suggested that lethal Babesia rodhaini infection in murine can be evaded by Babesia microti primary infection via activated macrophage-based immune response during the chronic stage of infection. However, whether the same immune dynamics occur during acute B. microti co-infection is not known. Hence, we used the mouse model to investigate the host immunity during simultaneous acute disease caused by two Babesia species of different pathogenicity. Results showed that B. microti primary infection attenuated parasitemia and conferred immunity in challenge-infected mice as early as day 4 post-primary infection. Likewise, acute Babesia co-infection undermined the splenic immune response, characterized by the significant decrease in splenic B and T cells leading to the reduction in antibody levels and decline in humoral immunity. Interestingly, increased macrophage and natural killer splenic cell populations were observed, depicting their subtle role in the protection. Pro-inflammatory cytokines (i.e. IFN-γ, TNF-α) were downregulated, while the anti-inflammatory cytokine IL-10 was upregulated in mouse sera during the acute phase of Babesia co-infection. Herein, the major cytokines implicated in the lethality caused by B. rodhaini infection were IFN- γ and IL-10. Surprisingly, significant differences in the levels of serum IFN- γ and IL-10 between co-infected survival groups (day 4 and 6 challenge) indicated that even a two-day delay in challenge infection was crucial for the resulting pathology. Additionally, oxidative stress in the form of reactive oxygen species contributed to the severity of pathology during acute babesiosis. Histopathological examination of the spleen showed that the erosion of the marginal zone was more pronounced during B. rodhaini infection, while the loss of cellularity of the marginal zone was less evident during co-infection. Future research warrants investigation of the roles of various immune cell subtypes in the mechanism involved in the protection of Babesia co-infected hosts.

In the early stage of coronavirus disease 2019 (COVID-19), most cases are identified as mild or moderate illnesses. Approximately 20% of hospitalised patients become severe or critical at the middle or late stage of the disease. The predictors and risk factors for prognosis in those with mild or moderate disease remain to be determined. Of 694 patients with COVID-19, 231 patients with mild or moderate disease, who were hospitalised at 10 hospitals in Wenzhou and nearby counties in China, were enrolled in this retrospective study from 17 January to 20 March 2020. The outcomes of these patients included progression from mild/moderate illness to severe or critical conditions. Among the 231 patients, 49 (21.2%) had a poor prognosis in the hospital. Multivariate logistic regression analysis showed that higher inflammation/coagulopathy/immunology responsive index (ICIRI=[c-reactive protein × fibrinogen × D-dimer]/CD8 T cell count) on admission (OR=345.151, 95% CI=23.014−5176.318) was associated with increased odds ratios for poor prognosis. The area under the receiver operating characteristic curve for ICIRI predicting severe and critical condition progression was 0.65 (95% CI=0.519−0.782) and 0.80 (95% CI=0.647−0.954), with cut-off values of 870.83 and 535.44, respectively. Conversely, age, sex, comorbidity, neutrophil/lymphocyte ratio, CD8 T cell count, and c-reactive protein, fibrinogen, and D-dimer levels alone at admission were not good predictors of poor prognosis in patients with mild or moderate COVID-19. At admission, a novel index, ICIRI, tends to be the most promising predictor of COVID-19 progression from mild or moderate illness to severe or critical conditions.

The novel coronavirus SARS-CoV-2 (causing the disease COVID-19) has caused a highly transmissible and ongoing pandemic worldwide. Due to its rapid development, next-generation sequencing plays vital roles in many aspects. Here, we summarize the current knowledge on the origin and human transmission of SARS-CoV-2 based on NGS analysis. The ACE2 expression levels in various human tissues and relevant cells were compared to provide insights into the mechanism of SAS-CoV-2 infection. Gut microbiota dysbiosis observed by metagenome sequencing and the immunogenetics of COVID-19 patients according to single-cell sequencing analysis were also highlighted. Overall, the application of these sequencing techniques could be meaningful for finding novel intermediate SARS-CoV-2 hosts to block interspecies transmission. This information will further benefit SARS-CoV-2 diagnostic development and new therapeutic target discovery. The extensive application of NGS will provide powerful support for our fight against future public health emergencies.