Extravascular spaces are the primary reservoir of antigenic diversity inTrypanosoma bruceiinfection

AbstractThe protozoan parasiteTrypanosoma bruceievades clearance by the host immune system through antigenic variation of its dense variant surface glycoprotein (VSG) coat, periodically “switching” expression of the VSG using a large genomic repertoire of VSG-encoding genes1–6. Studies of antigenic variation in vivo have focused near exclusively on parasites in the bloodstream5,7,8, but recent work has shown that many, if not most, parasites reside in the interstitial spaces of tissues9–13. We sought to explore the dynamics of antigenic variation in extravascular parasite populations using VSG-seq7, a high-throughput sequencing approach for profiling VSGs expressed in populations ofT. brucei. Here we show that tissues, not the blood, are the primary reservoir of antigenic diversity duringT. bruceiinfection, with more than 85% of VSGs found exclusively within extravascular spaces. We found that this increased diversity is correlated to slower parasite clearance in tissue spaces. Together, these data support a model in which the slower immune response in extravascular spaces provides more time to generate the antigenic diversity needed to maintain a chronic infection. Our findings reveal the important role that extravascular spaces can play in pathogen diversification.