Grant: Operating Grant

The colonic epithelium consists of both absorptive cells as well as secretory goblet cells that produce mucus. While many damaging agents, including bacterial pathogens target the epithelium, bacteria must first cross the sticky mucus layer that covers and protects these cells. It is currently unclear if the host immune system changes goblet cell function, in order for these cells to play a more active role in host defense. Considering that certain diarrhea causing bacterial pathogens, like enterohemorrhagic E. coli, (EHEC) colonize the gut epithelial surface, and thus reside within the mucus layer, we will address the impact of goblet cells and mucus on host defense using this family of pathogens. Since EHEC is human specific, we are using a related bacterial pathogen called Citrobacter rodentium that causes diarrhea and colitis in mice. Muc2 deficient mice lack an intestinal mucus layer and are highly susceptible to infection, carrying heavy C. rodentium burdens that are only loosely bound to the gut surface. As a result, these mice suffer excessive inflammation and bacterial translocation, leading to sepsis and death. In contrast, wildtype mice show increased mucus release during infection, which appears to protect the gut by flushing away loosely bound bacteria. Based on these studies, we will now examine how mucus actually protects the host. Since we also found that infection elevates the expression of RELM-B, another goblet cell derived mediator, and since RELM-B deficient mice suffer worsened infections, we will also explore RELM-B's role in host defense. Lastly, since subpopulations of C. rodentium do manage to cross the mucus barrier and colonize the intestinal surface, we will define the virulence strategies utilized by C. rodentium to overcome this host barrier. Taken together, our proposed studies will explore an important but understudied aspect of pathogen-host interactions at the mucosal surface that should aid in identifying new therapeutic targets.