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Virulence Jan 2020The mounting evidence supporting the capacity of to cause severe disease has prompted the need for a better characterization of the resulting clinical complications....
The mounting evidence supporting the capacity of to cause severe disease has prompted the need for a better characterization of the resulting clinical complications. India is making progress with reducing malaria, but epidemics of severe vivax malaria in Gujarat, one of the main contributors to the vivax malaria burden in the country, have been reported recently and may be the result of a decrease in transmission and immune development. Over a period of one year, we enrolled severe malaria patients admitted at the Civil Hospital in Ahmedabad, the largest city in Gujarat, to investigate the morbidity of severe vivax malaria compared to severe falciparum malaria. Patients were submitted to standard thorough clinical and laboratory investigations and only PCR-confirmed infections were selected for the present study. Severevivax malaria (30 patients) was more frequent than severe falciparum malaria (8 patients) in our setting, and it predominantly affected adults (median age 32 years, interquartile range 22.5 years). This suggests a potential age shift in anti-malarial immunity, likely to result from the recent decrease in transmission across India. The clinical presentation of severe vivax patients was in line with previous reports, with jaundice as the most common complication. Our findings further support the need for epidemiological studies combining clinical characterization of severe vivax malaria and serological evaluation of exposure markers to monitor the impact of elimination programmes.
Topics: Adolescent; Adult; Antimalarials; Child; Child, Preschool; Female; Humans; India; Malaria, Vivax; Male; Middle Aged; Plasmodium vivax; Prospective Studies; Severity of Illness Index; Young Adult
PubMed: 32490754
DOI: 10.1080/21505594.2020.1773107 -
Proceedings of the National Academy of... Jun 2020, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia. This conundrum is further complicated as...
, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia. This conundrum is further complicated as cytoadherence in the microvasculature is still a matter of investigations. Previous reports in , another parasite species shown to infect humans, demonstrated that variant genes involved in cytoadherence were dependent on the spleen for their expression. Hence, using a global transcriptional analysis of parasites obtained from spleen-intact and splenectomized monkeys, we identified 67 genes whose expression was spleen dependent. To determine their role in cytoadherence, two transgenic lines expressing two variant proteins pertaining to VIR and Pv-FAM-D multigene families were used. Cytoadherence assays demonstrated specific binding to human spleen but not lung fibroblasts of the transgenic line expressing the VIR14 protein. To gain more insights, we expressed five spleen-dependent genes as recombinant proteins, including members of three different multigene families (VIR, Pv-FAM-A, Pv-FAM-D), one membrane transporter (SECY), and one hypothetical protein (HYP1), and determined their immunogenicity and association with clinical protection in a prospective study of 383 children in Papua New Guinea. Results demonstrated that spleen-dependent antigens are immunogenic in natural infections and that antibodies to HYP1 are associated with clinical protection. These results suggest that the spleen plays a major role in expression of parasite proteins involved in cytoadherence and can reveal antigens associated with clinical protection, thus prompting a paradigm shift in biology toward deeper studies of the spleen during infections.
Topics: Animals; Antibodies, Viral; Antigens, Protozoan; Aotidae; CHO Cells; Cell Adhesion; Child; Cricetulus; Disease Models, Animal; Fibroblasts; Gene Expression Profiling; Genes, Protozoan; Host-Pathogen Interactions; Humans; Malaria, Vivax; Multigene Family; Papua New Guinea; Plasmodium vivax; Spleen; Splenectomy; Tissue Array Analysis
PubMed: 32439708
DOI: 10.1073/pnas.1920596117 -
Infection, Genetics and Evolution :... Aug 2024Plasmodium vivax Merozoite Surface Protein 8 (PvMSP8) is a promising candidate target for the development of multi-component vaccines. Therefore, determining the genetic...
Plasmodium vivax Merozoite Surface Protein 8 (PvMSP8) is a promising candidate target for the development of multi-component vaccines. Therefore, determining the genetic variation pattern of Pvmsp8 is essential in providing a reference for the rational design of the P. vivax malaria vaccines. This study delves into the genetic characteristics of the Pvmsp8 gene, specifically focusing on samples from the China-Myanmar border (CMB) region, and contrasts these findings with broader global patterns. The study uncovers that Pvmsp8 exhibits a notable level of conservation across different populations, with limited polymorphisms and relatively low nucleotide diversity (0.00023-0.00120). This conservation contrasts starkly with the high polymorphisms found in other P. vivax antigens such as Pvmsp1. A total of 25 haplotypes and 14 amino acid mutation sites were identified in the global populations, and all mutation sites were confined to non-functional regions. The study also notes that most CMB Pvmsp8 haplotypes are shared among Burmese, Cambodian, Thai, and Vietnamese populations, indicating less geographical variance, but differ notably from those found in Pacific island regions or the Panama. The findings underscore the importance of considering regional genetic diversity in P. vivax when developing targeted malaria vaccines. Non departure from neutral evolution were found by Tajima's D test, however, statistically significant differences were observed between the kn/ks rates. The study's findings are crucial in understanding the evolution and population structure of the Pvmsp8 gene, particularly during regional malaria elimination efforts. The highly conserved nature of Pvmsp8, combined with the lack of mutations in its functional domain, presents it as a promising candidate for developing a broad and effective P. vivax vaccine. This research thus lays a foundation for the rational development of multivalent malaria vaccines targeting this genetically stable antigen.
Topics: Plasmodium vivax; Selection, Genetic; Protozoan Proteins; Haplotypes; Humans; Genetic Variation; Malaria, Vivax; Mutation; Phylogeny; Antigens, Protozoan
PubMed: 38759940
DOI: 10.1016/j.meegid.2024.105605 -
Bulletin of Mathematical Biology Jul 2022Malaria is caused by Plasmodium parasites which are transmitted to humans by the bite of an infected Anopheles mosquito. Plasmodium vivax is distinct from other malaria...
Malaria is caused by Plasmodium parasites which are transmitted to humans by the bite of an infected Anopheles mosquito. Plasmodium vivax is distinct from other malaria species in its ability to remain dormant in the liver (as hypnozoites) and activate later to cause further infections (referred to as relapses). Mathematical models to describe the transmission dynamics of P. vivax have been developed, but most of them fail to capture realistic dynamics of hypnozoites. Models that do capture the complexity tend to involve many governing equations, making them difficult to extend to incorporate other important factors for P. vivax, such as treatment status, age and pregnancy. In this paper, we have developed a multiscale model (a system of integro-differential equations) that involves a minimal set of equations at the population scale, with an embedded within-host model that can capture the dynamics of the hypnozoite reservoir. In this way, we can gain key insights into dynamics of P. vivax transmission with a minimum number of equations at the population scale, making this framework readily scalable to incorporate more complexity. We performed a sensitivity analysis of our multiscale model over key parameters and found that prevalence of P. vivax blood-stage infection increases with both bite rate and number of mosquitoes but decreases with hypnozoite death rate. Since our mathematical model captures the complex dynamics of P. vivax and the hypnozoite reservoir, it has the potential to become a key tool to inform elimination strategies for P. vivax.
Topics: Animals; Anopheles; Humans; Malaria; Malaria, Vivax; Mathematical Concepts; Models, Biological; Models, Theoretical; Plasmodium vivax
PubMed: 35778540
DOI: 10.1007/s11538-022-01036-0 -
Frontiers in Cellular and Infection... 2021Severe thrombocytopenia can be a determinant factor in the morbidity of , the most widespread human malaria parasite. Although immune mechanisms may drive -induced...
Severe thrombocytopenia can be a determinant factor in the morbidity of , the most widespread human malaria parasite. Although immune mechanisms may drive -induced severe thrombocytopenia (PvST), the current data on the cytokine landscape in PvST is scarce and often conflicting. Here, we hypothesized that the analysis of the bidirectional circuit of inflammatory mediators and their regulatory miRNAs would lead to a better understanding of the mechanisms underlying PvST. For that, we combined Luminex proteomics, NanoString miRNA quantification, and machine learning to evaluate an extensive array of plasma mediators in uncomplicated patients with different degrees of thrombocytopenia. Unsupervised clustering analysis identified a set of PvST-linked inflammatory (CXCL10, CCL4, and IL-18) and regulatory (IL-10, IL-1Ra, HGF) mediators. Among the mediators associated with PvST, IL-6 and IL-8 were critical to discriminate subgroups, while CCL2 and IFN-γ from healthy controls. Supervised machine learning spotlighted IL-10 in -mediated thrombocytopenia and provided evidence for a potential signaling route involving IL-8 and HGF. Finally, we identified a set of miRNAs capable of modulating these signaling pathways. In conclusion, the results place IL-10 and IL-8/HGF in the center of PvST and propose investigating these signaling pathways across the spectrum of malaria infections.
Topics: Humans; Inflammation Mediators; Malaria, Vivax; MicroRNAs; Plasmodium vivax; Thrombocytopenia
PubMed: 33791239
DOI: 10.3389/fcimb.2021.631333 -
Frontiers in Cellular and Infection... 2021The unique biological features of not only make it difficult to control but also to eliminate. For the transmission of the malaria parasite from infected human to the...
The unique biological features of not only make it difficult to control but also to eliminate. For the transmission of the malaria parasite from infected human to the vector, gametocytes play a major role. The transmission potential of a malarial infection is inferred based on microscopic detection of gametocytes and molecular screening of genes in the female gametocytes. Microscopy-based detection methods could grossly underestimate the reservoirs of infection as gametocytes may occur as submicroscopic or as micro- or macro-gametocytes. The identification of genes that are highly expressed and polymorphic in male and female gametocytes is critical for monitoring changes not only in their relative proportions but also the composition of gametocyte clones contributing to transmission over time. Recent transcriptomic study revealed two distinct clusters of highly correlated genes expressed in the gametocytes, indicating that the male and female terminal gametocytogeneses are independently regulated. However, the detective power of these genes is unclear. In this study, we compared genetic variations of 15 and 11 genes expressed, respectively, in the female and male gametocytes among isolates from Southeast Asia, Africa, and South America. Further, we constructed phylogenetic trees to determine the resolution power and clustering patterns of gametocyte clones. As expected, 25 (PVP01_0616100) and 16 (PVP01_0305600) expressed in the female gametocytes were highly conserved in all geographical isolates. In contrast, genes including 6-cysteine protein (PVP01_0415800) and upregulated in late gametocytes (PVP01_1452800) expressed in the female gametocytes, as well as two CPW-WPC family proteins (PVP01_1215900 and PVP01_1320100) expressed in the male gametocytes indicated considerably high nucleotide and haplotype diversity among isolates. Parasite samples expressed in male and female gametocyte genes were observed in separate phylogenetic clusters and likely represented distinct gametocyte clones. Compared to 25, (PVP01_0415800) and a CPW-WPC family protein (PVP01_0904300) showed higher expression in a subset of Ethiopian samples. Thus, , , and CPW-WPC family proteins including PVP01_0904300, PVP01_1215900, and PVP01_1320100 could potentially be used as novel biomarkers for detecting both sexes of gametocytes in low-density infections and estimating transmission reservoirs.
Topics: Biomarkers; Humans; Malaria, Vivax; Phylogeny; Plasmodium vivax; Polymorphism, Genetic
PubMed: 35096643
DOI: 10.3389/fcimb.2021.789417 -
PLoS Neglected Tropical Diseases Jan 2023Extensive research has examined why some people have frequent Plasmodium falciparum malaria episodes in sub-Saharan Africa while others remain free of disease most of... (Review)
Review
Extensive research has examined why some people have frequent Plasmodium falciparum malaria episodes in sub-Saharan Africa while others remain free of disease most of the time. In contrast, malaria risk heterogeneity remains little studied in regions where P. vivax is the dominant species. Are repeatedly infected people in vivax malaria settings such as the Amazon just unlucky? Here, we briefly review evidence that human genetic polymorphism and acquired immunity after repeated exposure to parasites can modulate the risk of P. vivax infection and disease in predictable ways. One-fifth of the hosts account for 80% or more of the community-wide vivax malaria burden and contribute disproportionally to onward transmission, representing a priority target of more intensive interventions to achieve malaria elimination. Importantly, high-risk individuals eventually develop clinical immunity, even in areas with very low or residual malaria transmission, and may constitute a large but silent parasite reservoir.
Topics: Humans; Malaria, Vivax; Plasmodium vivax; Prevalence; Recurrence
PubMed: 36634044
DOI: 10.1371/journal.pntd.0011020 -
Frontiers in Immunology 2020Blood-feeding enriched gut-microbiota boosts mosquitoes' anti- immunity. Here, we ask how alters gut-microbiota, anti- immunity, and impacts tripartite...
Blood-feeding enriched gut-microbiota boosts mosquitoes' anti- immunity. Here, we ask how alters gut-microbiota, anti- immunity, and impacts tripartite -mosquito-microbiota interactions in the gut lumen. We used a metagenomics and RNAseq strategy to address these questions. In naïve mosquitoes, and spp. are the dominant bacteria and blood-feeding leads to a heightened detection of and . A parallel RNAseq analysis of blood-fed midguts also shows the presence of transcripts. After, infected blood-meal, however, we do not detect bacterial 16S rRNA until circa 36 h. Intriguingly, the transcriptional expression of a selected array of antimicrobial arsenal cecropins 1-2, defensin-1, and gambicin remained low during the first 36 h-a time frame when ookinetes/early oocysts invaded the gut. We conclude during the preinvasive phase, outcompetes midgut-microbiota. This microbial suppression likely negates the impact of mosquito immunity which in turn may enhance the survival of . Detection of sequences matching to mosquito-associated opens a new inquiry for its exploration as an agent for "paratransgenesis-based" mosquito control.
Topics: Animals; Anopheles; Gastrointestinal Microbiome; Plasmodium vivax; RNA-Seq; Symbiosis
PubMed: 32477320
DOI: 10.3389/fimmu.2020.00609 -
Cell Chemical Biology Jun 2020Plasmodium vivax infects hepatocytes to form schizonts that cause blood infection, or dormant hypnozoites that can persist for months in the liver before leading to...
Plasmodium vivax infects hepatocytes to form schizonts that cause blood infection, or dormant hypnozoites that can persist for months in the liver before leading to relapsing blood infections. The molecular processes that drive P. vivax schizont and hypnozoite survival remain largely unknown, but they likely involve a rich network of host-pathogen interactions, including those occurring at the host-parasite interface, the parasitophorous vacuole membrane (PVM). Using a recently developed P. vivax liver-stage model system we demonstrate that host aquaporin-3 (AQP3) localizes to the PVM of schizonts and hypnozoites within 5 days after invasion. This recruitment is also observed in P. vivax-infected reticulocytes. Chemical treatment with the AQP3 inhibitor auphen reduces P. vivax liver hypnozoite and schizont burden, and inhibits P. vivax asexual blood-stage growth. These findings reveal a role for AQP3 in P. vivax liver and blood stages and suggest that the protein may be targeted for therapeutic treatment.
Topics: Aquaporin 3; Cells, Cultured; Humans; Liver; Malaria, Vivax; Plasmodium vivax
PubMed: 32330444
DOI: 10.1016/j.chembiol.2020.03.009 -
Cell Host & Microbe Jul 2022Malaria-causing Plasmodium vivax parasites can linger in the human liver for weeks to years and reactivate to cause recurrent blood-stage infection. Although they are an...
Malaria-causing Plasmodium vivax parasites can linger in the human liver for weeks to years and reactivate to cause recurrent blood-stage infection. Although they are an important target for malaria eradication, little is known about the molecular features of replicative and non-replicative intracellular liver-stage parasites and their host cell dependence. Here, we leverage a bioengineered human microliver platform to culture patient-derived P. vivax parasites for transcriptional profiling. Coupling enrichment strategies with bulk and single-cell analyses, we capture both parasite and host transcripts in individual hepatocytes throughout the course of infection. We define host- and state-dependent transcriptional signatures and identify unappreciated populations of replicative and non-replicative parasites that share features with sexual transmissive forms. We find that infection suppresses the transcription of key hepatocyte function genes and elicits an anti-parasite innate immune response. Our work provides a foundation for understanding host-parasite interactions and reveals insights into the biology of P. vivax dormancy and transmission.
Topics: Hepatocytes; Humans; Liver; Malaria; Malaria, Vivax; Plasmodium vivax
PubMed: 35443155
DOI: 10.1016/j.chom.2022.03.034