Human immune response to primary cryptosporidiosis parallels murine infection models

Cryptosporidium is a protozoan parasite that causes cryptosporidiosis, an enteric infection associated with diarrhea, malnutrition, and impaired childhood development in low- and middle-income countries. Both humoral and cell-mediated immune responses have been implicated in protection, but the durability and quality of human immune responses in immunocompetent adults remain poorly defined. We investigated the development of immunity in two healthy US adults following primary cryptosporidiosis acquired during travel to Bangladesh. Longitudinal plasma samples were analyzed for antibody responses to Cryptosporidium antigens Cp17 and Cp23 and for circulating cytokine profiles. Circulating antibody peaked at three weeks post-infection but declined rapidly thereafter, approaching baseline within 16 weeks. In contrast, antibody avidity increased steadily over time, consistent with ongoing affinity maturation in germinal centers. While affinity maturation occurred, the composition memory B cells specific to Cryptosporidium antigens was skewed toward IgM+ cells across timepoints suggesting extrafollicular responses dominated and germinal center-derived, class-switched memory was limited. Cytokine profiling revealed an acute Th1-skewed response, with elevations in CXCL9, CXCL10, IL-27, IFNγ, IL-12, and IL-18 during early infection. These signatures mirrored protective pathways identified in murine models, underscoring the importance of type I immunity in parasite clearance. Together, these findings highlight that while antibody responses to Cryptosporidium are short-lived, avidity maturation persists, and Th1-driven cytokine responses dominate during acute infection. This work provides rare longitudinal data on immune responses in naïve adults following natural cryptosporidiosis and offers insight into mechanisms that may inform vaccine development and strategies to mitigate recurrent infection in vulnerable populations.