The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes

Abstract

Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria.

Distinct amino acid and lipid perturbations characterize acute versus chronic malaria

“…Previous studies have suggested that malaria parasites may exhibit multiple distinct metabolic phenotypes in vivo, including starvation states and normal glycolytic growth states, with variation in the expression of glycolysis, TCA cycle, and fatty acid metabolism genes (48)(49)(50). While these studies have not been conclusive in terms of which host environments trigger such variation in parasite metabolic states, in agreement with these previous studies, the present study also finds evidence of variation in TCA and fatty acid metabolism genes in vivo.…”

The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background

“…Specifically, it was proposed that the parasite cellular physiology could be (at least in part) controlled by fine-tuned transcriptional profiles of genes regulating active growth via glycolysis and/or alternative carbon source metabolism as well as other environmental stress responses. Distinct global transcriptional variations can also be associated with disease-related phenotypes such as malaria infection during pregnancy 36 , 37 and severe malaria with cerebral complications 38 , 39 . While pregnancy-associated malaria seems mainly associated with upregulation of genes encoding specific surface antigens (such as var and phist genes), the severe infections involve parasites with more complex transcriptional changes in processes such as energy metabolism, biosynthesis, protein synthesis and folding, and cytoadhesion.…”

Immune effector mechanisms in malaria: An update focusing on human immunity

“…Immune evasion strategies employed by P. falciparum have also been reviewed elsewhere . Other recent reviews explore the extent of genetic variation and gene expression in malaria parasites and how Plasmodium genomes and transcriptomes are now readily able to be sequenced and analysed . These technological advances are facilitating our ability to investigate human‐parasite interactions and led to the finding that vaccine‐induced antimalarial immunity is strain‐specific …”

“…15 Other recent reviews explore the extent of genetic variation and gene expression in malaria parasites 16 and how Plasmodium genomes and transcriptomes are now readily able to be sequenced and analysed. 17,18 These technological advances are facilitating our ability to investigate human-parasite interactions and led to the finding that vaccine-induced antimalarial immunity is strain-specific. 19 Understanding immune effector mechanisms in malaria-exposed individuals has been approached from two complementary perspectives: identifying mediators of immune-induced pathology and distinguishing them from those that confer protection.…”