Abstract
Background and Aims: Enteric infections trigger mucosal immune responses. However, whether such immune imprinting influences susceptibility to sterile inflammatory diseases like colitis remains unclear. The aims of this study were to investigate whether a resolved Citrobacter rodentium (CR) infection in mouse alters host susceptibility to chemically induced colitis and to identify the underlying immune mechanisms. Methods: C57BL/6 mice were infected with wild-type CR or CR lacking Map and EspF, a mutant lacking tight junction-disrupting effectors. 3 weeks post clearance, mice were subjected to dextran sodium sulfate (DSS)-induced colitis. Disease severity was assessed by weight change, colon length, histopathology, and myeloperoxidase levels. Colonic immune cell populations were characterised by flow cytometry, and cytokine levels were measured from colon explants. Functional roles of IL-17A were evaluated using recombinant cytokine administration and neutralising antibody treatment. Results: Mice that cleared CR infection fared better following DSS treatment compared to uninfected or CRdelMap_EspF-infected mice. This protective phenotype was not directly dependent on microbiota, as confirmed by co-housing experiments. Protected mice displayed elevated numbers of colonic Th1 and Th17 cells and higher levels of IL-17A, IL-22, and IL-2 cytokines. Prophylactic treatment with IL-17A conferred protection in naive mice, whereas IL-17A neutralisation in previously infected mice abrogated the benefit, identifying IL-17A as a key mediator of protection. Conclusions: Resolved intestinal infection with CR confers long-term protection against colitis via persistent IL-17A-mediated immune reprogramming. These findings resonate with the hygiene hypothesis and highlight how prior microbial exposure can shape mucosal resilience.
Keywords: Enteric infections, immune imprinting, Colitis
Competing Interest Statement
The authors have declared no competing interest.
Funder Information Declared
Wellcome TrustWellcome Trust, https://ror.org/029chgv08, 107057/z/15/z and 224282/Z/21/Z.