Helicobacter pylori infects the gastric tissue of approximately half of the world’s population, causing a spectrum of diseases ranging from gastritis to gastric ulcers and gastric cancer. It is well established that H. pylori manipulates the host’s immune system into mounting an ineffective yet chronic immune response, and that this immunosuppression facilitates lifelong persistence and disease progression. However, to date, a central mechanism utilised by H. pylori to mediate pan-immunosuppression to ultimately promote pathogenesis and establish lifelong colonisation remains unknown and was the focus of this study.
Here we show that interleukin-37, a powerful pan-immunosuppressive cytokine, is key to facilitating H. pylori-mediated broad immunosuppression and chronic persistence in the host. First, we examined human gastric biopsies obtained from H. pylori infected and non-infected individuals and found that IL-37 levels were significantly increased in the gastric tissues of H. pylori infected individuals compared to non-infected controls. Next, we confirmed the ability of H. pylori to induce the production of IL-37 by human gastric epithelial cells using a range of H. pylori clinical isolates, which resulted in a significant increase in IL-37 production by gastric epithelial cells compared to non-infected controls. Furthermore, using a range of reporter cell lines, we determined that IL-37 was produced by gastric epithelial cells in response to activation of a range of host innate immune receptors.
Next, we examined the role of IL-37 during H. pylori infection using transgenic mice expressing human IL-37. We found that IL-37 enhanced H. pylori colonisation while preventing the development of H. pylori-specific immune responses. Furthermore, we elucidated the multiple mechanisms whereby IL-37 functions to suppress primary human immune cells from both non-infected and H. pylori infected patients to ultimately promote pan-immunosuppression and prevent the development of an effective immune response.
Collectively, these findings reveal that H. pylori harnesses the potent immunosuppressive functions of IL-37 to promote colonisation, pan-immunosuppression and chronic persistence. These findings represent a critical advance in our understanding of H. pylori-mediated disease and identifies gastric IL-37 as a therapeutic target with enormous potential to combat H. pylori infection and H. pylori-mediated diseases, such as gastric cancer.