T cell responses in repeated controlled human schistosome infection compared to natural exposure

Schistosomiasis affects over 250 million people, predominantly in Sub-Saharan Africa. In Schistosoma -endemic regions a lack of natural sterilizing immunity means individuals are repeatedly infected, treated and reinfected. Due to difficulties in tracking infection in endemic areas, the kinetics of the host immune response during these reinfections have not been elucidated. Here, we use repeated (3x) controlled human Schistosoma mansoni ( Sm ) infection (repeated CHI) to directly study how antigen-specific T cells develop during reinfection. We compared these responses to natural Sm -infected endemic Ugandan individuals. We report that a mixed Th1/Th2/regulatory CD4 ⁺ T cell response develops in repeated CHI, primarily against adult worm antigens. Adult worm-specific responses after repeated CHI were similar to those observed in naturally infected endemic participants. However, endemic participants showed differential responses to antigens from the egg and cercariae life-cycle stages. Repeated CHI (3x) with sequential exposure to Sm cercariae of different sexes (male-female-male) revealed an elevated CD4 ⁺ T cell cytokine response to adult worm and egg antigens. Our findings demonstrate that reinfection with single-sex schistosomes elicits adult worm-specific T cell cytokine responses that reflect endemic-natural infection, highlighting the translatability of the CHI model to natural infection in endemic settings. Overall, this study advances our understanding of how schistosome immune responses develop over reinfection cycles in the human host, thereby increasing our understanding of the immunology of natural schistosome (re)infection.