title: Vector transmission regulates immune control of Plasmodium virulence.
abstract: Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria. Serial blood passage of Plasmodium through rodents, primates or humans increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host. In agreement, disease severity can be modified by vector transmission, which is assumed to 'reset' Plasmodium to its original character. However, direct evidence that vector transmission regulates Plasmodium virulence is lacking. Here we use mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi to interrogate regulation of parasite virulence. Analysis of SBP P. c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn modifies the elicited mammalian immune response, which in turn attenuates parasite growth and associated pathology. Attenuated parasite virulence associates with modified expression of the pir multi-gene family. Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence. These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine.
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Spence
authors.forename: William
authors.initials: W
authors.lastname: Jarra
authors.forename: Prisca
authors.initials: P
authors.lastname: Lévy
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Reid
authors.forename: Lia
authors.initials: L
authors.lastname: Chappell
authors.forename: Thibaut
authors.initials: T
authors.lastname: Brugat
authors.forename: Mandy
authors.initials: M
authors.lastname: Sanders
authors.forename: Matthew
authors.initials: M
authors.lastname: Berriman
authors.forename: Jean
authors.initials: J
authors.lastname: Langhorne
mesh_terms: D000818:Animals; D009033:Culicidae / Q000469:parasitology*; D004912:Erythrocytes / Q000469:parasitology; D006790:Host-Parasite Interactions / Q000276:immunology*; D007303:Insect Vectors / Q000469:parasitology*; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000635:transmission; D017780:Malaria Vaccines / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016788:Plasmodium chabaudi / Q000254:growth & development / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity*; D012692:Serial Passage; D014774:Virulence / Q000276:immunology
chemical_list: D017780:Malaria Vaccines