title: Severity of human african trypanosomiasis in East Africa is associated with geographic location, parasite genotype, and host inflammatory cytokine response profile.
abstract: The mechanisms underlying virulence in human African trypanosomiasis are poorly understood, although studies with experimental mice suggest that unregulated host inflammatory responses are associated with disease severity. We identified two trypanosomiasis foci with dramatically different disease virulence profiles. In Uganda, infections followed an acute profile with rapid progression to the late stage (meningoencephalitic infection) in the majority of patients (86.8%). In contrast, infections in Malawi were of a chronic nature, in which few patients progressed to the late stage (7.1%), despite infections of several months' duration. All infections were confirmed to be Trypanosoma brucei rhodesiense by testing for the presence of the serum resistance-associated (SRA) gene, but trypanosomes isolated from patients in Uganda or Malawi were distinguished by an SRA gene polymorphism. The two disease profiles were associated with markedly different levels of tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in plasma. In Uganda but not Malawi early-stage TNF-alpha was elevated, while in Malawi but not Uganda early-stage TGF-beta was elevated. Thus, rapid disease progression in Uganda is associated with TNF-alpha-mediated inflammatory pathology, whereas in the milder disease observed in Malawi this may be ameliorated by counterinflammatory cytokines. These differing host responses may result either from differing virulence phenotypes of northern and southern trypanosomes or from immune response polymorphisms in the different host populations.
authors.affiliation: School of Biological Sciences, University of Aberdeen, Zoology Building, Aberdeen AB24 2TZ, Scotland, United Kingdom.
authors.forename: Lorna
authors.initials: L
authors.lastname: MacLean
authors.forename: John E
authors.initials: JE
authors.lastname: Chisi
authors.forename: Martin
authors.initials: M
authors.lastname: Odiit
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Gibson
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ferris
authors.forename: Kim
authors.initials: K
authors.lastname: Picozzi
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Sternberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis*; D018450:Disease Progression; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D016833:Trypanosoma brucei rhodesiense / Q000145:classification* / Q000235:genetics; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C403774:serum resistance associated protein, Trypanosoma brucei