The impact of Helicobacter hepaticus infection on host immunity

Heawood, Anna Lucy Leith (2025) The impact of Helicobacter hepaticus infection on host immunity. PhD thesis, University of Glasgow.

Abstract

The mammalian immune system has evolved alongside a complex microbiota. Microbial colonization drives constant immune responses at steady state, while microbiota-derived metabolites and signals have functional impacts on host immune cells. Helicobacter hepaticus (Hh) is a member of the murine intestinal microbiota with the capacity to drive immune responses in a context-dependent manner. Hh stimulates strong immune regulation which counterbalances the induction of effector responses and allows persistent colonization without pathology. Whether these interactions alter how the host immune system responds in a subsequent disease setting has not previously been explored. In this thesis, we aimed to investigate how Hh affects the outcome of inflammatory disease and test whether Hh drives phenotypic and functional changes to intestinal immune cells at steady state.

Here, we demonstrate that Hh colonization attenuates intestinal disease severity in the DSS colitis model. This was dependent on extended colonization with Hh prior to colitis onset and was not present immediately following infection, suggesting a mechanism by which Hh primes intestinal immune responses at steady state to alter disease outcomes. We found that Hh colonization stimulated increased monocyte and neutrophil infiltration to the colon at steady state and drove increases to local proinflammatory cytokine transcription. However, colonic macrophages from infected mice showed suppressed cytokine responses ex vivo, indicating that Hh functionally modulates local immune cells to limit inflammatory responses. We tested whether the disease attenuating effect was dependent on recognition of Hh by TLR2, with the aim of elucidating the mechanism through which Hh affects disease outcomes. We demonstrate that disease attenuation does not require TLR2 signalling, suggesting that a different mechanism drives disease protection in Hh colonized animals.

This work provides insight into how host immune functions are shaped by the resident immunomodulatory microbiota. As the role of the microbiota in health and disease is becoming increasingly apparent, it is critical to develop a greater understanding of these interactions. Our work supports the conclusion that the microbiota primes the intestinal immune system at steady state, thereby altering immune responses during inflammatory settings.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology; Q Science > QR Microbiology > QR180 Immunology; Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Maloy, Professor Kevin
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85170
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 Jun 2025 14:07
• Last Modified: 10 Jun 2025 14:11
• Thesis DOI: 10.5525/gla.thesis.85170
• URI: https://theses.gla.ac.uk/id/eprint/85170