Interferon-gamma Mediated Host Responses to Enteric Pathogen, Citrobacter rodentium

Abstract

Diarrheal disease caused by attaching and effacing pathogens, such as enteropathogenic E. coli (EPEC), is a worldwide health concern. As the second leading cause of diarrheal-related death in young children, new investigations into host defense against EPEC, as well as future therapeutics, is greatly needed. To elucidate the host immune responses to these enteric pathogens, the attaching and effacing (A/E) murine pathogen, Citrobacter rodentium, has been widely used. It is well understood that C. rodentium infection induces a robust Th1 response within the host. Yet how these pleiotropic IFNγ immune responses are initiated, propagated, and the accessory immune cell types involved remains poorly understood. In this thesis, I investigated how innate immune cell types such as natural killer cells, which are significant producers of IFNγ, mediate these Th1 directed responses. This work identified that both NK and NK-like innate lymphoid type 1 cells (ILC1s) are capable of producing IFNγ in response to C. rodentium, and NK cells rapidly increase in numbers within the colon during the early stages of infection. Depletion of these cell types causes a delayed Th1 CD4+ T cell response within the colon, resulting in increased bacterial load, and greater degree of colonic pathology at later time points. Additionally, depletion of these cells results in decreased CXCL9 chemokine expression in mice. I later determined that CXCL9 exhibited direct antimicrobial action against Citrobacter in vitro. Depletion of this chemokine in vivo, in the absence of adaptive immune responses, or its receptor CXCR3, results in increased mortality rates, elevated bacterial loads, greater degree of pathology, and deeper penetration of bacteria within the colonic crypts. These data indicate a potential direct antimicrobial role for this IFNγ-induced chemokine, independent of its known properties for the homing of T cells to the site of infection. These findings demonstrate the importance of accessory IFNγ-producing immune cells in not only mediating Th1 CD4+ T cells responses, but also other innate host defense mechanisms against A/E pathogens.