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

Abstract

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease rapidly expand in naive hosts, we found no transcriptional evidence to support this hypothesis. These data indicate that parasite variants that dominate severe malaria do not have an intrinsic growth or survival advantage; instead, they presumably rely upon infection-induced changes in their within-host environment for selection.

Expression Patterns of Plasmodium falciparum Clonally Variant Genes at the Onset of a Blood Infection in Malaria-Naive Humans

“…Considering that individual parasites express a single var gene, this result indicates that the parental population was relatively homogeneous, such that the vast majority of individual parasites expressed the same var gene ( var2csa ), whereas after passage through transmission stages the population became heterogeneous, with different individual parasites expressing different var genes. Some of the most highly expressed var genes in vNF54 lines coincided with the most highly expressed genes in a recent CHMI study using the 3D7 line to infect volunteers ( 52 ) ( Fig. S3A ), and preferential upregulation of type B var genes in parasites from the volunteers is also consistent with previous reports from other CHMI studies ( 36 , 48 , 52 ).…”

“…Some of the most highly expressed var genes in vNF54 lines coincided with the most highly expressed genes in a recent CHMI study using the 3D7 line to infect volunteers ( 52 ) ( Fig. S3A ), and preferential upregulation of type B var genes in parasites from the volunteers is also consistent with previous reports from other CHMI studies ( 36 , 48 , 52 ).…”

“…2B and C ). Analysis of the Cy5 values revealed that var2csa was the predominantly expressed var gene in pNF54, whereas in vNF54 lines, multiple var genes were expressed at intermediate levels, similar to findings from previous CHMI studies ( 36 , 38 , 48 , 52 ) ( Fig. S2C ).…”

“…Two more recent studies analyzed the transcriptome of parasites obtained from CHMI volunteers at a genome-wide level. However, these studies only included ring-stage parasites, precluding the characterization of transcriptional patterns for genes expressed at other stages of the IDC ( 51 , 52 ).…”

Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites

“…The algorithm was developed here specifically to determine whether any metabolites could be identified that changed in abundance in similar ways across a series of distinct fever-associated diseases. These include Zika virus infection in patients from Ecuador [13], Leishmaniasis patients from Spain [14] and uncomplicated malaria infected volunteers from the UK [15]. The samples had all been run previously using the same LC-MS platform (Glasgow Polyomics, University of Glasgow, UK).…”