Spatially and Genetically Distinct African Trypanosome Virulence Variants Defined by Host Interferon‐γ Response

Abstract

We describe 2 spatially distinct foci of human African trypansomiasis in eastern Uganda. The Tororo and Soroti foci of Trypanosoma brucei rhodesiense infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and hostimmune response. In particular, infections with the Tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage and higher plasma interferon (IFN)-␥ concentration, compared with those with the Soroti genotype. We propose that the magnitude of the systemic IFN-␥ response determines the time at which infected individuals develop central nervous system infection and that this is consistent with the recently described role of IFN-␥ in facilitating blood-brain barrier transmigration of trypanosomes in an experimental model of infection. The identification of trypanosome isolates with differing disease progression phenotypes provides the first field-based genetic evidence for virulence variants in T. brucei rhodesiense.

Increased acute immune response during the meningo-encephalitic stage of Trypanosoma brucei rhodesiense sleeping sickness compared to Trypanosoma brucei gambiense

“…Similar differences had already been shown within the T. b. rhodesiense subspecies [52]. CRP and ORM1, the most interesting proteins in our study, did not show any statistical difference between patients affected by the same form of HAT but enrolled in different countries.…”

Role for Parasite Genetic Diversity in Differential Host Responses toTrypanosoma bruceiInfection

“…This phenotype, with respect to T. congolense, has been examined in cattle (50,51) and laboratory mice (48,49), and genetic loci involved in host control of trypanosome infections have been identified in both host systems (20,32). Host genetic variation is also implicated in differences in the severity of human African trypanosomiasis (11,39). In contrast, the potential impact of parasite genetic variation upon disease severity and progression has received less attention.…”

“…However, there is also a range of clinical outcomes within these two subspecies: for example, the "mild" and "severe" T. b. rhodesiense disease observed in geographically different foci (63). Different parasite genotypes have been identified (23) and suggested to be associated with human African trypanosomiasis foci differing in severity between distinct geographical regions, such as Malawi and Uganda (38) but also within a relatively restricted geographical area of Uganda (39). Although this provides strong circumstantial evidence for a spec-trum of pathogenesis influenced by parasite variation, this divergence of clinical signs could potentially be due to the host or other, as-yet-undetermined, factors (39).…”

Discovery and Verification of Osteopontin and Beta-2-microglobulin as Promising Markers for Staging Human African Trypanosomiasis

“…Most of the efforts focused on cytokines and chemokines, because the patient's immune system plays a crucial role in the brain pathology (11)(12)(13)(14).…”