The role of T cell derived cytokines in Helicobacter pylori and other gastrointestinal infections.

Background and Innovation. Chronic infections and the inflammation associated with long-term immune activation contribute to carcinogenesis in several tissues, especially gastrointestinal infections. Specifically, Helicobacter pylori infection has been formally recognized as a Type I carcinogen for over many years. More recently, associations between bacterial infections and colorectal cancer have been made (i.e. enterotoxigenic Bacteroides fragilis, pks+ E. coli, F. nucleatum). We use H. pylori as a highly relevant, rigorous and tractable model to investigate an understudied area of host-pathogen interactions, bacterial-driven carcinogenesis. There is an unmet need to understand the dichotomy that exists between immune responses; those that are needed to control infection versus those that drive chronic inflammation. Our published observations indicate that T cell cytokines, especially IL-17 signaling, play a key role controlling H. pylori infection, maintaining the gastric barrier, and preventing exacerbated T and B cell responses (e.g. Th1 responses and antibody production). Importantly, we have found that H. pylori infection outcomes in the absence of IL-17RA are pathologically worse, which is paradoxical to the view that IL-17 is pro-carcinogenic in several tissues. Our data indicate that IL-17RA deficient mice progress to gastric cancer more rapidly. This is clinically relevant for in humans with gastric cancer, higher levels of IL-17RA in gastric tissue is a positive prognostic marker for survival. We will test the hypothesis that IL- 17 and IFNJ (a Th1 cytokine) have divergent roles activating fibroblasts, resulting in protective versus detrimental outcomes, respectively. Our laboratory is uniquely positioned to work at this intersection of inflammation, cancer, and bacterial pathogenesis. This allows us to view the role of the immune response during infection induced cancers through an innovative lens. Two aims are proposed which will utilize in vivo animal models and in vitro organoid-fibroblast co-cultures combined with imaging, flow cytometry, and transcriptomics approaches. We will investigate how proinflammatory T cell cytokines remodel fibroblast function in the context of H. pylori induced inflammation and injury/carcinogenesis. The influence of IL-17 and IFNJ on several fibroblast functions will be investigated. These functions include immune cell recruitment, antigen presentation and modulation of T cell activities, and epithelial cell reconstitution and repair. The impact of antibiotic treatment and administration of a gastric protectant will be considered as mechanisms to enhance tissue repair and prevent gastric cancer development. Significance and Impact to Veterans Healthcare. It is now estimated that infectious pathogens (including bacteria, viruses and parasites) account for the development of at least 20% of all human tumors. Gastrointestinal cancers are now defined as presumptive from serving in the Gulf Wars and are covered under the PACT act. With Gulf War serving veterans aging, this highlights the need to identify new treatment strategies. These cancers are among the most diagnosed cancers (5th (gastric) and 3rd (colorectal)). Further, since 2003, the VA has considered stomach cancer a service-connected malignancy especially for service members who were exposed to ionizing radiation. Unfortunately, gastric cancer has a relatively low survival rate and is not often diagnosed early, highlighting a need for better risk stratification. Path to Translation/Implementation The completion of these aims will contribute to our understanding of host factors which impact carcinogenesis. With discussion of host-modulating immunotherapeutics (i.e. anti-PD1, anti-IL17) as GI cancer treatments, it is imperative that we understand the balance between infection control and inflammation control. Further, these studies will highlight pathways which should be modulated by pharmaceuticals or natural gastroprotectants Project Number: 2I01BX000915-13A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: HOLLY ALGOOD | Institution: VETERANS HEALTH ADMINISTRATION, NASHVILLE, TN | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 INFB-K (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11176731