All ETDs from UAB

Advisory Committee Chair

Casey T Weaver

Advisory Committee Members

Charles O Elson III

Hui Hu

Laurie E Harrington

Robert S Welner

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Intestinal infections are a cause of morbidity and mortality worldwide and remain a public threat. Interleukin (IL)-22 is central to host immune responses in the intestine during infection and inflammation. IL-22 can be produced by both innate and adaptive immune cells, yet their relative contributions to host protection remain unclear. Here we demonstrated the specific role and mechanism for IL-22 from innate and adaptive sources to protect the host. Using the Citrobacter rodentium (C.r) model, we found that IL-22 from innate cell, protect the host during early infection. IL-22 induces epithelial production of polymorphonuclear neutrophils (PMN) recruiting chemokine CXCL1, CXCL2 and CXCL5 through IL-22 receptor signaling on intestinal epithelial cells, to promote PMN recruitment into the colon during early infection. We showed that PMN protects the host by limiting C.r load and preventing crypt invasion. PMNs are recruited to both intestinal epithelium and lamina propria during infection and prevent C.r from invading colonic crypts. We also found that IL-22 from CD4+ T cells is important during the late phase response. Uniquely, mice with IL-22 deficiency from CD4+ T cells suffered massive C.r invasion into the colonic crypts. In line with this, we found IL-22 provided more systematic IV activation of STAT3 at both surface and cryptal epithelial cells, and IL-22 producing CD4+ T cells are located in close proximity to colonic crypt cells. CD4+ T cell derived IL-22 activates host-protective transcriptome programs from intestinal epithelial cells, including AMPs and chemokines. Lastly, our research specified the role of IL-22 mediated antimicrobial responses during C.r infection. We found Lcn2 protects the host by limiting bacterial load during early infection. Since PMNs are required for host protection against C.r and are recruited by the IL-22 response, we examined the role of neutrophil elastase (NE) and ROS production, in C.r infection. We found NE protects the host from early infection by limiting C.r load and prevent C.r from invading the crypt region. Meanwhile, NOX2 mediated ROS production is required to protect the host from fatality caused by C.r infection. We also found IL-22 induced iNOS production is required for bacterial load control during early infection.

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