title: Parasite genetic diversity does not influence TNF-mediated effects on the virulence of primary rodent malaria infections.
abstract: The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) is associated with malaria virulence (disease severity) in both rodents and humans. We are interested in whether parasite genetic diversity influences TNF-mediated effects on malaria virulence. Here, primary infections with genetically distinct Plasmodium chabaudi chabaudi (P.c.c.) clones varied in the virulence and cytokine responses induced in female C57BL/6 mice. Even when parasitaemia was controlled for, a greater day 7 TNF-alpha response was induced by infection with more virulent P.c.c. clones. Since many functions of TNF-alpha are exerted through TNF receptor 1 (TNFR1), a TNFR-1 fusion protein (TNFR-Ig) was used to investigate whether TNFR1 blockade eliminated clone virulence differences. We found that TNFR-1 blockade ameliorated the weight loss but not the anaemia induced by malaria infection, regardless of P.c.c. clone. We show that distinct P.c.c. infections induced significantly different plasma interferon gamma (IFN-gamma), interleukin 6 (IL-6) and interleukin 10 (IL-10) levels. Our results demonstrate that regardless of P.c.c. genotype, blocking TNFR1 signalling protected against weight loss, but had negligible effects on both anaemia and asexual parasite kinetics. Thus, during P.c.c. infection, TNF-alpha is a key mediator of weight loss, independent of parasite load and across parasite genotypes.
authors.affiliation: Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland. grainne.long@ed.ac.uk
authors.forename: G H
authors.initials: GH
authors.lastname: Long
authors.forename: B H K
authors.initials: BH
authors.lastname: Chan
authors.forename: J E
authors.initials: JE
authors.lastname: Allen
authors.forename: A F
authors.initials: AF
authors.lastname: Read
authors.forename: A L
authors.initials: AL
authors.lastname: Graham
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006790:Host-Parasite Interactions; D008288:Malaria / Q000276:immunology / Q000469:parasitology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology; D016788:Plasmodium chabaudi / Q000145:classification / Q000235:genetics / Q000472:pathogenicity*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014774:Virulence; D015431:Weight Loss
chemical_list: D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha