Common virulence gene expression in adult first-time infected malaria patients and severe cases

Abstract

Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected adult travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis of PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naïve immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.

Transcriptome Analysis of Plasmodium falciparum Isolates From Benin Reveals Specific Gene Expression Associated With Cerebral Malaria

“…Although var genes domains expression associated with CM has been extensively studied [ 13 , 17 , 18 ], the involvement of other parasite factors is not yet fully understood. Previous studies have shown that parasites display distinct gene expression profiles associated with severe malaria (SM) [ 5 , 6 ]. A more metabolically quiescent phenotype associated with SM was demonstrated [ 5 ].…”

“…A more metabolically quiescent phenotype associated with SM was demonstrated [ 5 ]. In addition, deregulated genes implicated in var genes expression or Pf EMP1 presentation to the iE membrane were identified [ 5 , 6 ]. In this study, we aimed to characterize P falciparum isolates’ gene expression in the context of pediatric malaria, by comparing the whole transcriptome of isolates from Beninese children enrolled in the NeuroCM study.…”

Plasmodium falciparum Parasite Lines Expressing DC8 and Group A PfEMP1 Bind to Brain, Intestinal, and Kidney Endothelial Cells

“…PfEMP1 proteins have diverged in binding activity for CD36 and EPCR (Smith et al, 2013). Whereas previous work has linked EPCR or dual EPCR and ICAM-1 PfEMP1 variants to severe malaria (Lavstsen et al, 2012;Turner et al, 2013;Bernabeu et al, 2016;Kessler et al, 2017;Storm et al, 2019; Sahu Wichers et al, 2021), little is known about their endothelial binding specificity. Here, we provide evidence that the DC8 and Group A EPCR-binding PfEMP1 subsets have binding activity for brain, gut, and kidney endothelial cells.…”

“…For instance, different subsets of PfEMP1 proteins encode binding activity for CD36 (Robinson et al, 2003;Hsieh et al, 2016), endothelial protein C receptor (EPCR) (Turner et al, 2013;Lau et al, 2015), and intercellular adhesion molecule 1 (ICAM-1) (Smith et al, 2000;Lennartz et al, 2019). Whereas the EPCR binders comprise only a small minority of the var gene repertoire (~10% of genes) (Rask et al, 2010), this subset is transcriptionally elevated in severe malaria infections and both the DC8 and Group A PfEMP1 variants are linked to severe malaria complications (Lavstsen et al, 2012;Turner et al, 2013;Bernabeu et al, 2016;Kessler et al, 2017;Lennartz et al, 2017;Mkumbaye et al, 2017;Sahu et al, 2021;Wichers et al, 2021). From in vitro studies, EPCR-binding variants adhere to human brain endothelial cells (Turner et al, 2013;Avril et al, 2016;Lennartz et al, 2017;Bernabeu et al, 2019;Storm et al, 2019) and to primary human heart and lung microvascular endothelial cells (Avril et al, 2013;Gillrie et al, 2015), suggesting they may have broad affinity for diverse microvascular beds.…”

Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria

“…It is not clear whether sST2 affects endothelial activation, endothelial activation affects sST2 levels, or if interactions occur both ways. Animal studies or studies of an in vitro blood-brain barrier could help to determine this [ 49 ]. Plasma sST2 levels may also, or instead, serve as a marker of brain injury, elevated as a specific response to cerebral ischemia and serving as a marker of neuroinflammation [ 19 ].…”