Modulation of colonocyte barrier function and signaling by cytomegalovirus infection

The colonic epithelium provides an essential barrier between the colonic lumen and the body, and defects in the barrier have been associated with inflammatory bowel disease and colitis. Human cytomegalovirus (CMV) infects 40-90% of the United States population, depending upon age and race, and latent infection persists for the lifetime of the individual. In the case of the GI tract, reactivation of CMV infection in IBD patients and cancer patients, especially those who are receiving immunosuppressive treatment, can result in severe colitis which can lead to shock, colectomy, or mortality. However, how this infection impacts the epithelium of the colon and its barrier function, differentiation, and signaling is unknown. Because the colonic epithelium is the first barrier to the leakage of antigens and immune cells, understanding how the epithelium is impacted by this virus is fundamental to understanding CMV colitis. However, little is known about how the CMV changes the biology of the mucosal epithelium. The goal of this application is to expand our understanding of the impact of CMV on colonic tight junctions, Erk and YAP signaling, proliferation, and differentiation into the multiple cell types of the colonic epithelium to understand the underlying basis of CMV colitis. These studies are fundamental to the identification of pathways that are exploited by the virus to cause disease and could provide insights that lead to therapeutic targets.