Vitamin A Mediated Protection From Gastrointestinal Infection

Nutritional status, immune function, and the gut microbiota are all factors in protection against gut infection. Citrobacter rodentium causes a gastrointestinal (Gl) infection in mice that models foodborne infections with enteropathogenic Escherichia coli in humans. The goal of this project is to determine how vitamin A deficiency worsens and intervention with the vitamin A metabolite retinoic acid (RA) affords protection against C. rodentium infection. Our preliminary data show that vitamin A deficiency (A-) resulted in a chronic C. rodentium infection that was lethal in 40% of the A- mice. In contrast, chronically
infected A- mice treated with RA were able to clear the infection. Here we will determine the mechanisms by which vitamin A deficiency results in failure to clear infection and RA helps to resolve this GI infection. We hypothesize that vitamin A/RA is required for protection mediated by: 1) T cells, 2) intestinal epithelial cells, and 3) maintaining homoeostasis of the gut microbiota. Our approach includes the use of vitamin A deficient and adequate mice, and A- mice treated with RA, and the use of 3 novel animal models: mice lacking retinoid signaling in T cells or in intestinal epithelial cells specifically, and germfree mice. Mice with a tissue-specifi dominant negative RA receptor will be used to block retinoid signaling selectively in T cells (aim 1) and intestinal epithelial cells (aim 2) to probe mechanisms by which vitamin A controls GI infection. Methods to be used will include imaging of bioluminescent C. rodentium to localize the bacteria in the intestine and immunological and histological methods to characterize cell types, functions and tissue histopathology. In addition, germfree mice will be used to determine the role of the microbiota in the vitamin A-mediated protection from C. rodentium (aim 3). It is expected that resolution of C. rodentium infection (clearance) will require vitamin A signaling in both intestinal T cells and epithelium as well as maintaining homeostasis of gut microbiota. Understanding the mechanisms by which vitamin A deficiency and RA intervention regulate these processes will be critical for informing public health messages as well as for the possible use of vitamin A/RA for protection from GI infection.