Expression of the Plasmodium falciparum Clonally Variant clag3 Genes in Human Infections

Abstract

Background. Many genes of the malaria parasite Plasmodium falciparum show clonally variant expression regulated at the epigenetic level. These genes participate in fundamental host-parasite interactions and contribute to adaptive processes. However, little is known about their expression patterns during human infections. A peculiar case of clonally variant genes are the 2 nearly identical clag3 genes, clag3.1 and clag3.2, which mediate nutrient uptake and are linked to resistance to some toxic compounds.Methods. We developed a procedure to characterize the expression of clag3 genes in naturally infected patients and in experimentally infected human volunteers.Results. We provide the first description of clag3 expression during human infections, which revealed mutually exclusive expression and identified the gene predominantly expressed. Adaptation to culture conditions or selection with a toxic compound resulted in isolate-dependent changes in clag3 expression. We also found that clag3 expression patterns were reset during transmission stages.Conclusions. Different environment conditions select for parasites with different clag3 expression patterns, implying functional differences between the proteins encoded. The epigenetic memory is likely erased before parasites start infection of a new human host. Altogether, our findings support the idea that clonally variant genes facilitate the adaptation of parasite populations to changing conditions through bet-hedging strategies.

Plasmodium falciparumpopulation genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

“…When we compared the similarity in other variant antigen families, we observed variation depending on the specific gene family. Invasion genes were largely conserved, except for the Clag gene family—in which some gene family members are known to vary even within clones of the same genetic strain [31–33] (Figure S10C). Stevor transcription was also extremely similar for all members of the cluster, with very few significant differences observed (Figure S10D).…”

Complex nutrient channel phenotypes despite Mendelian inheritance in a Plasmodium falciparum genetic cross

“…Although transfection to produce C3h-KO indicates that CLAG3 is not needed for in vitro propagation, the conservation and variable expansion of the clag3 clade in Plasmodium spp. suggest a more essential role under in vivo conditions in vertebrate infections [27,29,33]. In light of PSAC's role in nutrient uptake [14], we hypothesized that the high concentrations of most nutrients in standard RPMI 1640-based media may permit growth of the CLAG3-null parasite but that the lower levels in host plasma may prove inadequate.…”

“…Although parasite multigene families typically use gene switching for immune evasion [32], an interesting alternative proposal is that switching between the two clag3 genes alters channel properties and enables optimal nutrient uptake that can respond to the human host's nutritional status [33]. Because these proteins are broadly acknowledged drug and vaccine targets [14,21,34,35], these and various other questions about the RhopH complex and the roles of the member proteins in intracellular parasite development will require concerted study.…”

<p>Immunoinformatics and Vaccine Development: An Overview</p>

“…Studies have tried to understand the "languages" of the antigenic variant of PfEMP1 proteins. 97,101,102 They sought to know the PfEMP1 proteins binding properties or search to understand the correlation between motifs and infection severity.…”