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Title: Diverse clinical responses in Trypanosoma brucei rhodesiense human African trypanosomiasis : genetic variation in parasitic virulence or host immuno-genetics?
Author: MacLean, Lorna
ISNI:       0000 0001 3615 7155
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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Diverse clinical responses have been reported in geographically distinct Trypanosoma brucei rhodesiense Human African Trypanosomiasis (HAT) foci giving rise to the idea that HAT manifests as a chronic disease in southern East African countries and increases in virulence towards the north. To study the significance of host and parasite genetics on disease severity in HAT I assessed the clinical and cytokine profiles of 275 HAT patients recruited in two northern foci (Uganda) and one southern focus (Malawi) between 1998 and 2003.  This data was correlated to patient ethno-linguistic group, host genotype by analysis of immune response gene polymorphisms and trypanosome genotype by analysis of microsatellite and minisatellite loci. T. brucei in northern and southern HAT foci were distinguished by a polymorphism in the serum resistance-associated gene (SRA C-M/K) which was associated with striking differences in disease pathology and cytokine profiles.  The SRA C-K polymorphism was associated with elevated TGF-β and mild disease phenotype in Malawi while the SRA C-M polymorphism was associated with dramatically elevated CSF IL-10 and IL-6, severe neuropathy and outcome in Uganda, suggesting trypanosome genotypes, by their varying ability to regulate host immune responses, caused different levels of disease severity in northern and southern foci. Within Uganda patient ethno-linguistic group was associated with marked differences in disease severity; in particular Western and Eastern Nilotic groups displayed increased disease severity and higher mortality rates which were associated with high CSF IFN-γ, IL-6 and IL-10 indicating differences in CNS immune response between ethno-linguistic groups.  Furthermore, genotype frequencies at locus IL-10-1082 significantly differed between the Western Nilotic and Bantu patient groups suggesting variation in host immuno-genetics may also play a role in HAT disease severity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available