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Methods to Investigate the Regulatory Role of Small RNAs and Ribosomal Occupancy of Plasmodium falciparum
Published on: December 4, 2015
The molecular basis of coordinated antigen switching enabling chronic infection by human malaria parasites
Joseph E Visone1, Francesca Florini1, Evi Hadjimichael1
1Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
Abstract:
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 parasite's 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.
Insights
The malaria parasite Plasmodium falciparum evades immunity by switching its surface proteins. This study reveals how var2csa acts as a switching hub, coordinating gene expression to prolong infections.
Area of Science:
- Malariology
- Molecular Parasitology
- Epigenetics
Background:
- Plasmodium falciparum virulence stems from infected red blood cell adhesion and antigenic variation via PfEMP1 proteins.
- PfEMP1 variants are encoded by the multi-copy var gene family, with expression switching enabling parasite survival.
- var gene expression is epigenetically controlled, but the triggers for switching remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which var2csa facilitates transcriptional switching in Plasmodium falciparum.
- To understand how var2csa integrates the var gene family into a coordinated network for chronic infection.
Main Methods:
- Investigated the role of noncoding RNAs in var gene regulation.
- Analyzed the function of an upstream open reading frame in var2csa expression.
- Examined the involvement of the nonsense mediated mRNA decay pathway in var gene switching.
Main Results:
- Noncoding RNAs, an upstream open reading frame, and nonsense mediated mRNA decay interact to regulate var gene expression.
- var2csa functions as a transiently activated switching hub, coordinating the var gene network.
- This coordinated network perpetuates chronic Plasmodium falciparum infections.
Conclusions:
- var2csa acts as a central regulator of var gene switching through a novel mechanism involving RNA regulation and decay pathways.
- The coordinated regulation of var genes by var2csa is crucial for the persistence of malaria infections.
- Understanding this switching mechanism offers potential targets for novel anti-malarial strategies.
