Discussion

Asymptomatic carriers of pathogens are an often overlooked impediment to the control and elimination of many diseases. One such disease is Human African trypanosomiasis (HAT), an economically important disease of sub-Saharan Africa in which a serologically positive but asymptomatic reservoir population has recently been identified. Our study aimed to understand the genetic underpinnings of the asymptomatic phenotype by analysing the transcriptomes of immune cells from both symptomatic HAT patients and asymptomatic individuals to identify functional groups, pathways, local expression quantitative trait loci (eQTL) and polymorphisms associating with HAT susceptibility. This analysis implicated T cell activation and the major histocompatibility (MHC) locus as factors affecting HAT disease outcome. We verified this in a mouse model for trypanosomiasis, demonstrating that blocking T cell activation reduces parasitaemia and improves animal condition, mimicking the human asymptomatic phenotype and demonstrating a clear link from genetics to disease outcome. Understanding how asymptomatic individuals control infection and the role T cell activation plays in the phenomenon will lead to the development of interventions that alleviate symptoms in symptomatic HAT patients and also allow individuals more likely to develop disease to be identified and pre-emptively treated.