RT Journal Article SR Electronic T1 T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis JF bioRxiv FD Cold Spring Harbor Laboratory SP 184762 DO 10.1101/184762 A1 Paul Capewell A1 Bruno Bucheton A1 Caroline Clucas A1 Hamidou Ilboudo A1 Anneli Cooper A1 Taylor-Anne Gorman A1 Kerry O’Neill A1 Agapitos Patakas A1 Andrew Platt A1 Heli Vaikkinen A1 William Weir A1 Mamadou Camara A1 Paul Garside A1 Vincent Jamonneau A1 Annette MacLeod YR 2017 UL http://biorxiv.org/content/early/2017/09/05/184762.abstract AB Infections by many pathogens can result in a wide range of phenotypes, from severe to mild, or even asymptomatic. Understanding the genetic basis of these phenotypes can lead to better tools to treat patients or detect reservoirs. To identify human genetic factors that contribute to symptoms diversity, we examined the range of disease severities caused by the parasite T. b. gambiense, the primary cause of human African trypanosomiasis (HAT). We analyzed the transcriptomes of immune cells from both symptomatic HAT cases and individuals with latent infections. Our analysis identified several genes and pathways that associated with the latent phenotype, primarily suggesting increased T and B cell activation in HAT patients relative to latent infections. We also used these transcriptome data to conduct an exome-wide single nucleotide polymorphism (SNP) association study. This suggested that SNPs in the human major histocompatibility locus (HLA) associate with severity, supporting the transcription data and suggesting that T cell activation is a determining factor in outcome. Finally, to establish if T cell activation controls disease severity, we blocked co-stimulatory dependent T cell activation in an animal model for HAT. This showed that reducing T cell activation during trypanosome infection improves symptoms and reduces parasitemia. Our data has used a combination of transcriptome-wide analysis and an in vivo model to reveal that T cell activation and the HLA locus associate with the development of symptoms during HAT. This may open new avenues for the development of new therapeutics and prognostics.