Innate immunological contributions to severe C. rodentium infection
File(s)
Author(s)
Baghshomali, Yasaman
Type
Thesis
Abstract
The mouse pathogen Citrobacter rodentium (C. rodentium) is a commonly used model of infectious, caused by pathogenic Escherichia coli, and non-infectious, such as Inflammatory Bowel Disease (IBD), gut inflammation or colitis. Two different mouse models are used in this model, with C57BL/6 (C57) mice developing a self-limiting disease considered to be mild while C3H/HeNCrl (C3H) mice succumb to infection and represent a severe model of infection that more closely resembles life-threatening human infection and IBD flare ups. In order to further our understanding of the subjacent mechanisms involved in these distinct responses to the same pathogen, this project commenced by characterizing the innate immunological differences between mild and severe disease. This was done through the analysis of immune cell recruitment and colonic cytokine production following C. rodentium infection, where C3H mice were found to have significantly higher recruitment of neutrophils to the colon following infection compared to C57 mice. This coincided with increased neutrophil production in the bone marrow of C3H mice and increased serum G-CSF. To understand the intrinsic differences that may be responsible for these marked differences, an analysis of the proteomic signatures of recruited colonic neutrophils was carried out for each mouse strain; interestingly the most significant difference was an enrichment in proteins involved in NET formation in C57 mice. In an attempt to understand the contributions of intestinal epithelial cells (IECs) in this increased recruitment of neutrophils to the colon during the early stages of severe infection, the IEC proteome at 3 days post infection was also investigated. Antigen presentation and processing, a pathway associated with initiation of the adaptive immune response, was found to be significantly upregulated at this early time point, corresponding to an early increase of IFN-g in colonic explants, which is a key regulator of antigen processing and presentation. Together, this study reveals important innate immunological contributions to severe C. rodentium infection that could provide future insight into the mechanisms involved in the development of severe colitis.
Version
Open Access
Date Issued
2022-07
Date Awarded
2022-11
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Frankel, Gad
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)