Restricted (Penn State Only)
Snyder, Lindsay M
Graduate Program:
Immunology and Infectious Diseases
Doctor of Philosophy
Document Type:
Date of Defense:
March 22, 2018
Committee Members:
  • Margherita Teresa-Anna Cantorna, Dissertation Advisor
  • Margherita Teresa-Anna Cantorna, Committee Chair
  • Girish Soorappa Kirimanjeswara, Committee Member
  • Na Xiong, Committee Member
  • A Catharine Ross, Outside Member
  • vitamin A
  • retinoic acid
  • intestine
  • T cell
  • innate immunity
  • adaptive immunity
  • Intestinal epithelial cell
  • infection
  • inflammation
  • Citrobacter rodentium
  • intestinal permeability
  • neutrophil
  • macrophage
Vitamin A deficiency (A-) affects millions of children in resource limited countries, and is associated with increased childhood morbidity and mortality due to severe enteric infections. Similarly, it was observed that A- mice were susceptible to the murine enteric pathogen, Citrobacter rodentium. In humans and mice, vitamin A supplementation and retinoic acid (RA) dosing (respectively) were protective and promoted host survival. The first objective was to determine the mechanism of RA mediated protection in A- mice and the importance of retinoid signaling in T cells during C. rodentium infection. First, I characterized immunological changes in the colons of vitamin A sufficient (A+), A-, and RA treated A- mice (A- RA). A+ mice had significantly more IL-17 secreting cells, a majority of which were CD4+ T cells. A- mice had fewer colonic IL17+ cells, but RA dosing induced CD11b+ cell mediated production of IL17, which was associated with host survival and resolution of infection. Mice lacking retinoid signaling in T cells (T-dnRAR mice) did not succumb to C. rodentium infection; however, most became chronically infected and neither early nor late RA dosing induced clearance of the infection. Additionally, I showed that A+, A-, and A- RA had different intestinal immune populations and serum and liver metabolic profiles. These findings indicated that being A- can have long term immunological and metabolic effects that cannot be corrected through RA supplementation. These data also demonstrated that RA regulates CD11b+ mediated production of IL-17a in A- mice and that retinoid signaling in T cells was required for host resistance to C. rodentium. The second objective was to inhibit retinoid signaling in intestinal epithelial cells (IECs, villin dnRAR mice) and determine the effects on intestinal immunity and barrier function. IECs are critical for intestinal immunity and homeostasis: IECs absorb nutrients and water, provide a physical barrier between the host and luminal contents, and engage in signaling cross-talk with intraepithelial lymphocytes. RA signaling in IECs was required to maintain intestinal TCRαβ CD8αα populations. In A+ mice, loss of retinoid signaling in IECs had no effect on host susceptibility to C. rodentium infection. After exposure to dextran sodium sulfate (DSS), A+ villin dnRAR mice had mild increases in intestinal permeability compared to A+ WT littermates. In A- mice however, loss of RA signaling in IECs resulted in extremely high mortality rates in response to C. rodentium infection and significantly increased weight loss and intestinal permeability after DSS exposure. Together, the work presented in this dissertation demonstrates that retinoid signaling is more important for regulating innate and adaptive immune cell function, not IECs, that is required for host defense against enteric infection and resolution of chemically-induced colonic damage. I also show that A+, A-, and A- RA hosts are phenotypically distinct, and that early vitamin A deficiency may have long term, deleterious effects on immunity and metabolism that cannot be resolved with RA supplementation.