Author ORCID Identifier

https://orcid.org/0000-0001-5794-0587

Semester

Summer

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Jonathan T. Busada

Committee Co-Chair

Mariette Barbier

Committee Member

Mariette Barbier

Committee Member

Karen Martin

Committee Member

Salik Hussain

Committee Member

Timothy Eubank

Abstract

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide, affecting millions of people. H. pylori is the strongest risk factor for gastric cancer, with about 90% of the cases strongly associated with H. pylori infection. Half of the world's population is infected with this bacterium. However, only a small subset of the infected population (1-3 %) go on to develop gastric cancer. Diagnosis of the disease at an early stage is the biggest challenge because of the widespread prevalence of H. pylori infection and a long asymptomatic phase before the advanced stages. Patients are left with limited treatment options when the infection progresses to an advanced form of pathology. Chronic inflammation is a necessary driving factor for advancing the infection and development of cancer.

H. pylori triggers the infiltration of different types of immune cells, among which the neutrophils, macrophages, dendritic cells, and eosinophils are the primary responders. T cells are also necessary for adequate bacterial clearance. Among these, macrophages are critical to phagocytose bacteria and present antigens to the cells of the adaptive immune system. Previous studies from our lab showed that in the absence of circulating glucocorticoids, macrophages promote gastritis and the development of metaplasia, a pre-neoplastic lesion, in mice. Glucocorticoid signaling is critical for the innate immune sensitization and resolution of inflammation. Although glucocorticoids are popularly known as immunosuppressive compounds, there is an abundance of literature on the immune-sensitizing role of glucocorticoid signaling. Glucocorticoids are known to regulate a large number of gene sets in monocytes during differentiation and dictate macrophage transcriptome. Here, we hypothesize that loss of the endogenous glucocorticoid signaling during differentiation impairs the macrophage's immune response to the bacterium H. pyloriand affects the development of gastric cancer. Using ATAC and RNA sequencing, we elucidated that loss of the glucocorticoid receptor (GR) during differentiation blunts the macrophage immune responses towards H. pylori and skews them to cancer pathways. Further, we investigate the role of glucocorticoids within the myeloid compartment during gastric carcinogenesis using the model of Helicobacter pylori and Helicobacter felis infection in mice. We observed that loss of GR signaling impairs gastric leukocyte infiltration and T-cell homing in H. pylori-infected myGRKO mice. Additionally, myGRKO mice were protected from robust gastric inflammation and metaplasia in the chronic H. felis infection model. Our findings suggest that glucocorticoid signaling has an immunomodulatory role in the immune compartment and is required for a normal immune response to H. pylori infection

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