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 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 promotes H. pylori-mediated immunosuppression and chronic persistence. We found that IL-37 was highly expressed in gastric biopsies obtained from H. pylori infected individuals compared to non-infected controls. Infection of human gastric epithelial cells and gastric organoids with clinical isolates of H. pylori confirmed the ability of H. pylori to induce the production of IL-37 by epithelial cells. Using transgenic mice, we found that IL-37 enhanced H. pylori-mediated pathogenesis while preventing the development of an effective immune response. Furthermore, we elucidated the mechanisms whereby IL-37 functions to inhibit primary immune cell functions to ultimately prevent the development of an effective immune response against H. pylori infection.
Collectively, these findings reveal that H. pylori harnesses the potent immunosuppressive functions of IL-37 to promote colonisation, immunomodulation and chronic persistence. Our 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 gastric cancer.