Biology subjects

Hadjimichael, E.

Publications and source records attributed to Hadjimichael, E..

2 recordsLinked to original sources

bioRxiv2025

The molecular basis of coordinated antigen switching enabling chronic infection by human malaria parasites

The exceptional virulence of the human malaria parasite, Plasmodium falciparum, is in large part attributed to the adhesive properties of infected red blood cells and the parasites ability to avoid antibody recognition through antigenic variation. Both properties are derived from a hypervariable protein placed on the infected cell surface called PfEMP1, different versions of which are encoded by members of the multi-copy var gene family. Over the course of an infection, rising and falling waves of parasitemia correspond to transcriptional switching between var genes, with parasites expressing alternative PfEMP1 isoforms replacing those eliminated by antibodies targeting the previously expressed PfEMP1. var gene expression is controlled epigenetically, however what triggers transcriptional switching and determines which genes are activated is largely unknown. Previous work implicated a unique, universally conserved gene called var2csa as a central component in transcriptional switching, however the molecular basis for its role was obscure. Here we describe how noncoding RNAs, an upstream open reading frame and the nonsense mediated mRNA decay pathway interact to enable var2csa to function as a transiently activated "switching hub" that unifies the var gene family into a single coordinated network, thereby perpetuating chronic infections.

microbiology↗

bioRxiv2024

Transcriptional plasticity of virulence genes provides malaria parasites with greateradaptive capacity for avoiding host immunity

Chronic, asymptomatic malaria infections contribute substantially to disease transmission and likely represent the most significant impediment preventing malaria elimination and eradication. Plasmodium falciparum parasites evade antibody recognition through transcriptional switching between members of the var gene family, which encodes the major virulence factor and surface antigen on infected red blood cells. This process can extend infections for up to a year; however, infections have been documented to last for over a decade, constituting an unseen reservoir of parasites that undermine eradication and control efforts. How parasites remain immunologically "invisible" for such lengthy periods is entirely unknown. Here we show that in addition to the accepted paradigm of mono-allelic var gene expression, individual parasites can simultaneously express multiple var genes or enter a state in which little or no var gene expression is detectable. This unappreciated flexibility provides parasites with greater adaptive capacity than previously understood and challenges the dogma of mutually exclusive var gene expression. It also provides an explanation for the antigenically "invisible" parasites observed in chronic asymptomatic infections.

microbiology↗