Helicobacter pylori-induced immune priming requires type I interferon signaling.

Helicobacter pylori (H. pylori) infection induces persistent colonization and chronic inflammation, yet the mechanisms by which bacterial exposure establishes sustained inflammatory responses remain incompletely understood. We previously demonstrated that priming human monocytes with viable, but not heat-killed H. pylori, establishes immune priming, characterized by a heightened response to subsequent LPS challenge. Here, we delineate the signaling pathways that establish this inflammatory adaptation. Unbiased whole-cell proteomics identified type I and type II interferon (IFN) signaling as the dominant pathways distinguishing monocytes exposed to viable versus heat-killed bacteria. Consistently, viable H. pylori, but not heat-killed or PFA-inactivated bacteria, activated IFN signaling and imprinted LPS hyper-responsiveness. Manipulating IFN signaling at the time of LPS challenge did not modify this hypersensitivity, whereas blocking type I IFN signaling during priming markedly attenuated the hyperresponsiveness. Accordingly, supplementation with type I, but not type II IFN, during priming restored hypersensitivity in monocytes exposed to PFA-inactivated H. pylori. Interestingly, type I IFN only partially restored LPS-hypersensitivity in monocytes exposed to heat-killed H. pylori, indicating that heat inactivation interferes with additional signaling cues derived from intact bacteria, which are required to drive the full hyper-responsiveness to LPS. Collectively, our findings identify type I IFN as a central regulator of H. pylori-induced immune priming and reveal a previously unrecognized mechanism by which H. pylori infection programs persistent inflammatory adaptation in host immune cells through type I IFN signaling.