Friday, April 26, 2024
4/26/2024
Mouse models are widely used to study the pathogenesis of idiopathic inflammatory bowel disease. It is clear that germ free mice are protected against the development of disease, which is consistent with the prevailing hypothesis that IBD patients develop inappropriate immune responses directed against their own intestinal microbiota. However, it is also clear that lymphopenic mice housed in barrier facilities with complex intestinal microbiota do not develop disease, and disease penetrance in KO strains of mice with aberrant regulatory T cell function, such as interleukin-10 KO mice, is highly dependent on the composition of their intestinal microbiota. Helicobacter hepaticus is a bacterial species that is sufficient, but not necessary, to trigger IBD in barrier-maintained KO mouse strains. We have focused on characterizing the pathogenesis of H. hepaticus in IBD-prone mice in order to better understand the mechanisms driving mucosal inflammation in these models, with the goal of gaining better perspective on the etiopathogenesis of IBD. In KO mouse models, H. hepaticus triggers innate immune responses that lead to progressive mucosal inflammation in the absence of Treg suppression. In contrast, normal immunocompetent mice develop lifelong persistent infection with H. hepaticus that leads to specific immunity without eradication and without the development of pathologic lesions or clinical signs of disease in the GI tract. Persistent subclinical infection with H. hepaticus delays recovery from infectious colitis however. Because enterohepatic Helicobacter species are so widely distributed in research mouse colonies, it is important to define the mechanism by which subclinical Helicobacter infection influences the nature and severity of colitis. Likewise, better characterization of the mechanism by which H. hepaticus infection triggers innate immune activation leading to IBD in KO mouse strains will allow for better understanding of how these models relate to human IBD, and will provide insight into why candidate preventive and therapeutic interventions succeed or fail in preclinical trials. We will focus on bacterial-host interactions that lead to parallel induction of Treg and activation of innate immunity in order to broadly define the mechanisms by which H. hepaticus influences disease outcome in both immunocompetent and KO mouse strains. To accomplish this, 3 specific aims will address (i) immunomodulation of colitis in immunocompetent mice, (ii) detailed mechanistic characterization of innate immune activation, and (iii) in vivo pathogenesis of IBD in mice with defective Treg function, all using the prototypic enterohepatic Helicobacter species H. hepaticus.
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