Meta-analysis of Plasmodium falciparum var Signatures Contributing to Severe Malaria in African Children and Indian Adults

Abstract

The clinical presentation of severePlasmodium falciparummalaria differs between children and adults, but the mechanistic basis for this remains unclear. Contributing factors to disease severity include total parasite biomass and the diverse cytoadhesive properties mediated by the polymorphicvargene parasite ligand family displayed on infected erythrocytes. To explore these factors, we performed a multicohort analysis of the contribution ofvarexpression and parasite biomass to severe malaria in two previously published pediatric cohorts in Tanzania and Malawi and an adult cohort in India. Machine learning analysis revealed independent and complementary roles forvaradhesion types and parasite biomass in adult and pediatric severe malaria and showed that similarvarprofiles, including upregulation of group A and DC8var, predict severe malaria in adults and children. Among adults, patients with multiorgan complications presented infections with significantly higher parasite biomass without significant differences invaradhesion types. Conversely, pediatric patients with specific complications showed distinctvarsignatures. Cerebral malaria patients showed broadly increased expression ofvargenes, in particular group A and DC8var, while children with severe malaria anemia were classified based on high transcription of DC8varonly. This study represents the first large multisite meta-analysis ofvarexpression, and it demonstrates the presence of commonvarprofiles in severe malaria patients of different ages across distant geographical sites, as well as syndrome-specific disease signatures. The complex associations between parasite biomass,varadhesion type, and clinical presentation revealed here represent the most comprehensive picture so far of the relationship between cytoadhesion, parasite load, and clinical syndrome.IMPORTANCEP. falciparummalaria can cause multiple disease complications that differ by patient age. Previous studies have attempted to address the roles of parasite adhesion and biomass in disease severity; however, these studies have been limited to single geographical sites, and there is limited understanding of how parasite adhesion and biomass interact to influence disease manifestations. In this meta-analysis, we compared parasite disease determinants in African children and Indian adults. This study demonstrates that parasite biomass and specific subsets ofvargenes are independently associated with detrimental outcomes in both childhood and adult malaria. We also explored how parasitevaradhesion types and biomass play different roles in the development of specific severe malaria pathologies, including childhood cerebral malaria and multiorgan complications in adults. This work represents the largest study to date of the role of bothvaradhesion types and biomass in severe malaria.

Mapping immune variation and var gene switching in naive hosts infected with Plasmodium falciparum

“…The potential role of parasite factors in influencing immune variation has not yet been explored in CHMI. Expression of a subset of parasite variant surface antigens (VSA) known as group A and DC8 var genes is associated with severe malaria in both children and adults ( Duffy et al, 2019 ; Jespersen et al, 2016 ; Kyriacou et al, 2006 ; Lavstsen et al, 2012 ; Tonkin-Hill et al, 2018 ; Warimwe et al, 2012 ). These virulence-associated genes encode PfEMP1 adhesion molecules that mediate sequestration of infected red cells in the microvasculature.…”

New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria

“…Quantitative measurements of plasma levels of the malarial protein, histidine-rich protein 2 (HRP2), have shown to predict progression to CM [27]. A recent metaanalysis reports that parasite biomass, as determined by parasitemia and quantitiative plasma HRP2 levels, and parasite var gene profiles are predictors of progression to SM in both adults and children [28]. Furthermore, in vitro findings using patient parasite isolates, support the theory that there is an association between parasite binding affinity to specific endothelial receptors in different tissues and disease pathology [29].…”

“…We direct the reader to more in-depth reviews looking at cytoadherence adjunctive therapies [2,19]. Since parasite biomass is also a predictor of progression to SM [28], whole blood transfusions and automated erythrocyte exchange, to decrease parasitemia, have been used as putative adjunctive therapies, although no randomized clinical trials have confirmed their superiority over the standard of care (reviewed in [39]). Additionally, due to cost and availability, these strategies are often untenable in most low-resource settings [2].…”

“…Additionally, due to cost and availability, these strategies are often untenable in most low-resource settings [2]. If parasite phenotypes are reproducibly found to predict progression to SM, then parasite isolate genotyping could be exploited to risk-stratify malaria patients [28]. However, technical and financial constraints associated with genotyping at point-of-care in low-resource settings make this an unattractive approach at present.…”

Analysis of Spleen Histopathology, Splenocyte composition and Hematological Parameters in Mice Infected withPlasmodium bergheiK173

“…The percentages of macrophages in ICR infected mice were lower than uninfected mice, and the parasitemia was higher than falciparum. There is a natural and complex variation in the pathogenesis and clinical presentation of malaria, which is influenced by host age, immunity and genetic background, as well as by environmental conditions and parasite genetics (2,3). Host immunity and genetic factors are estimated to account for one quarter of the total variability in malaria severity (4,5).…”