Abstract
Citrobacter rodentium is an intestinal mouse pathogen widely used as a model to study the mucosal response to infection. Inbred mouse strains suffer one of two fates following infection: self-limiting colitis or fatal diarrheal disease. We previously reported that Rspo2 is a major genetic determinant of the outcome of C. rodentium infection; Rspo2 induction during infection of susceptible mice leads to loss of intestinal function and mortality. Rspo2 induction does not impact bacterial colonization, but rather, impedes the ability of the host to tolerate C. rodentium infection. Here, we performed deep RNA sequencing and systematically analyzed the global gene expression profiles of C. rodentium-infected colon tissues from susceptible and resistant congenic mice strains to determine the common responses to infection and the Rspo2-mediated dysfunction pathway signatures associated with loss of disease tolerance. Our results highlight changes in metabolism, tissue remodeling, and host defence as common responses to infection. Conversely, increased Wnt and stem cell signatures, loss of epithelial differentiation, and exaggerated CD4+ T cell activation through increased antigen processing and presentation were specifically associated with the response to infection in susceptible mice. These data provide insights into the molecular mechanisms underlying intestinal dysfunction and disease tolerance during C. rodentium infection.
Highlights
Citrobacter rodentium is a natural mouse pathogen that infects the large intestine and causes colitis and characteristic thickening of the colonic mucosa[1]
We previously discovered a novel pathway in susceptible mice (e.g. C3H/HeOuJ, AKR, FVB) that leads to the development of fatal diarrheal disease during C. rodentium infection through Rspo2-mediated disruption of intestinal homeostasis[3]
principal component analysis (PCA) revealed three distinct clusters: uninfected controls, infected susceptible mice, and infected resistant mice, indicating that samples are closely grouped according to mouse strain and infection status, and that few transcriptomic differences are observed between strains prior to infection (Fig. 1)
Summary
Citrobacter rodentium is a natural mouse pathogen that infects the large intestine and causes colitis and characteristic thickening of the colonic mucosa[1]. To avoid any confounding genetic and phenotypic differences between divergent inbred strains, we developed a congenic mouse strain that is on a pure C3H/HeOuJ ( called C3Ou) susceptible background but carries a segment of chromosome 15 encompassing Rspo[2] and its regulatory region from resistant C57BL/6 mice[6] These resistant congenic mice exhibit complete survival following C. rodentium infection compared to susceptible C3Ou mice which suffer 100% mortality. We previously demonstrated that bacterial loads and infection kinetics are identical in susceptible C3Ou and resistant congenic mice[6], a phenomenon that is not observed when comparing different susceptible and resistant inbred strains[9] This indicates that Rspo[2] does not affect bacterial colonization or replication but rather the ability of the host to establish disease tolerance in the presence of pathogenic bacteria in the intestine. Our work provides an unbiased, global perspective of the common and differential host response to infection and provides new insights into the underlying mechanisms regulating intestinal homeostasis versus dysfunction
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