Cryptosporidium spp. are opportunistic protozoan parasites that infect epithelial cells of the small
intestine, causing diarrheal illness in humans. In immunodeficient individuals, the disease can be severe,
chronic and even fatal. In both adults and children, the disease can range from asymptomatic to severe.
These differences in susceptibility and disease severity are known to be due in part to immunological
status of the host, malnutrition, or prior exposure. But one important factor that has had limited study, is
the role microbiota plays in host resistance. While differences in microbiota have been linked to
susceptibility, it is not clear which bacterial microbiota profiles are important in resistance and which might
pre-dispose individuals to infections or to more severe disease. It is also not understood how altered
microbiota changes the metabolic profile in the intestinal tract and how this impacts the immune response
of the host. Our long-term goal is to understand the underlying gut environment and how that may be
related to susceptibility and severity of infection. Our objective is to determine how differences in
microbiota affect resistance and susceptibility to infections and to determine if overall patterns or profiles
can be identified. Additionally, we plan to determine if there is an association between changes in
bacterial metabolites and infection levels. The central hypothesis in this proposal is that differences in
the microbiota alter susceptibility and host immune response to C. parvum infection which allow for
greater expansion of the organism. We will test this hypothesis by treating mice with different antibiotics
and a repurposed drug known to alter the intestinal flora and examine how these changes affect
susceptibility, infection level, and host immune responses, particularly activation of T cells and cytokine
response in the local environment. The rationale for this hypothesis is based on the our preliminary data
that show that there are significant changes in the microbiome of mice treated with certain antibiotics
compared to vehicle control mice, which results in increased susceptibility. Additionally, metabolic
analyses will be performed to determine changes in short chain fatty acid levels, amino acids and lipids.
We will correlate difference in metabolites to susceptibility and growth. These changes may subsequently
alter the immune response and microbiota-associated metabolites that result in modulation of local T
cells and secretion of key cytokines, such as IFN-¿. These findings would be significant because it would
help advance the understanding of mechanisms underlying the expansion of cryptosporidiosis during
conditions of increased vulnerability. In addition, by identifying microbiota profiles in individuals that are
at greater risk of infection (e.g immunodeficient individuals, transplant recipients, and young children),
interventions could be administered to bolster or alter the microbiota to a more resistant profile.