title: Epigenetic dysregulation of virulence gene expression in severe Plasmodium falciparum malaria.
abstract: Chronic infections with the human malaria parasite Plasmodium falciparum depend on antigenic variation. P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major erythrocyte surface antigen mediating parasite sequestration in the microvasculature, is encoded in parasites by a highly diverse family of var genes. Antigenic switching is mediated by clonal variation in var expression, and recent in vitro studies have demonstrated a role for epigenetic processes in var regulation. Expression of particular PfEMP1 variants may result in parasite enrichment in different tissues, a factor in the development of severe disease. Here, we study in vivo human infections and provide evidence that infection-induced stress responses in the host can modify PfEMP1 expression via the perturbation of epigenetic mechanisms. Our work suggests that severe disease may not be the direct result of an adaptive virulence strategy to maximize parasite survival but that it may indicate a loss of control of the carefully regulated process of antigenic switching that maintains chronic infections.
authors.affiliation: School of Life Sciences, Keele University, Staffs ST5 5BG, United Kingdom.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Merrick
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.forename: Caroline
authors.initials: C
authors.lastname: Buckee
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.forename: Natalia
authors.initials: N
authors.lastname: Gomez-Escobar
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
mesh_terms: D057890:Epigenomics; D015870:Gene Expression / Q000235:genetics; D055786:Gene Knockout Techniques; D006790:Host-Parasite Interactions; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D016778:Malaria, Falciparum / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000235:genetics* / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics*; D037761:Sirtuins / Q000235:genetics*; D016615:Telomere / Q000378:metabolism; D013696:Temperature; D014158:Transcription, Genetic; D014774:Virulence / Q000235:genetics
chemical_list: D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D019344:Lactic Acid; D037761:Sirtuins