Cryptosporidiosis and Oral Tolerance

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ABSTRACT Cryptosporidiosis is an important cause of diarrheal disease in young children in the developing world where it causes significant mortality and morbidity. Children that present with symptomatic disease are more likely to suffer from malnutrition and lower height and weight per age, and these deficiencies persist for years after the primary infection resolves. Surprisingly even asymptomatic cases can be associated with malnutrition and failure to thrive for several years beyond the initial infection. These findings suggest that alterations in intestinal function during the initial infection establish persistent enteropathy that stunts development. However, the cellular and molecular mechanisms driving this clinical outcome remain unresolved. During early development of the intestine, Goblet cells play a critical role in sampling of antigens from the gut lumen in a process that generates peripheral T regulatory cells (pTreg), which suppress immune responses to dietary antigens and commensals. This early process in shaping the mucosal immune system is critical to maintenance of oral tolerance later in life. Our study examines the intriguing hypothesis that cryptosporidiosis in early life alters responses to lumenal antigens by disrupting oral tolerance that normally develops during this time period. In preliminary studies we have shown that neonatal mice, which are highly susceptible to C. parvum infection, show defects in Goblet cell functions related to antigenic sampling. Furthermore we show that C. parvum infected neonatal mice have reduced development of pTreg cells. We will explore the hypothesis that cryptosporidiosis disrupts oral tolerance through two main aims: 1) determine the molecular mechanism for disruption of antigen sampling by Goblet cells, 2) explore the consequence of disrupted pTreg development on oral tolerance. These studies will explore how altered immune responses to dietary antigens or commensal organisms drive inflammation that impairs gut function following enteric infection.