Protein Malnutrition Impairs Intestinal Epithelial Cell Turnover, a Potential Mechanism of Increased Cryptosporidiosis in a Murine Model

Abstract

Malnutrition and cryptosporidiosis form a vicious cycle and lead to acute and long-term growth impairment in children from developing countries. Insights into mechanisms underlying the vicious cycle will help to design rational therapies to mitigate this infection. We tested the effect of short-term protein malnutrition on Cryptosporidium parvum infection in a murine model by examining stool shedding, tissue burden, and histologic change and explored the mechanism underlying the interaction between malnutrition and cryptosporidiosis through immunostaining and immunoblotting. Protein malnutrition increased stool shedding and the number of intestine-associated C. parvum organisms, accompanied by significant suppression of C. parvum-induced caspase 3 activity and expression of PCNA and Ki67, but activation of the Akt survival pathway in intestinal epithelial cells. We find that even very brief periods of protein malnutrition may enhance (or intensify) cryptosporidiosis by suppressing C. parvum-induced cell turnover and caspase-dependent apoptosis of intestinal epithelial cells. This implicates a potential strategy to attenuate C. parvum's effects by modulating apoptosis and promoting regeneration in the intestinal epithelium.