Challenging trypanosome antigenic variation paradigms using natural systems (360G-Wellcome-206815_Z_17_Z)

Antigenic variation (AV) is a common mechanism used by pathogens to evade host immunity and ensure infection chronicity. Recently the capacity to study AV at a molecular and population-level has expanded through systems level approaches. However, there is urgent need to challenge existing paradigms by assessing temporal (early vs. chronic infection) and spatial (tissue compartment) influences on the pathogen antigen repertoire, as well as pathogen genotype and host context. Here, we will quantitate and derive models to parameterize antigen diversity and infection chronicity in African trypanosomes. These are an exemplar of AV where population-scale antigen mRNA sequencing is tractable and underlying molecular regulators of infection are identified and manipulable. Critically, we will extend the trypanosome AV paradigm beyond the limited infection model commonly used to date, i.e. Trypanosoma brucei in mice. Thus, we will (i) quantitate the contributors to AV in chronic bovine infections for the clinically-relevant pathogens T. congolense and T. vivax, relating this to conventional infections in mice (ii) determine the contribution of identified molecular regulators of AV, parasite development and tissue compartmentation, and (iii) use the derived information to build mathematical models to interpret and unify molecular and population-level understanding of AV in these clinically-relevant infections.