Immunity against Moraxella catarrhalis requires guanylate‐binding proteins and caspase‐11‐NLRP3 inflammasomes.

Moraxella catarrhalis is an important human respiratory pathogen and a major causative agent of otitis media and chronic obstructive pulmonary disease. Toll‐like receptors contribute to, but cannot fully account for, the complexity of the immune response seen in M. catarrhalis infection. Using primary mouse bone marrow‐derived macrophages to examine the host response to M. catarrhalis infection, our global transcriptomic and targeted cytokine analyses revealed activation of immune signalling pathways by both membrane‐bound and cytosolic pattern‐recognition receptors. We show that M. catarrhalis and its outer membrane vesicles or lipooligosaccharide (LOS) can activate the cytosolic innate immune sensor caspase‐4/11, gasdermin‐D‐dependent pyroptosis, and the NLRP3 inflammasome in human and mouse macrophages. This pathway is initiated by type I interferon signalling and guanylate‐binding proteins (GBPs). We also show that inflammasomes and GBPs, particularly GBP2, are required for the host defence against M. catarrhalis in mice. Overall, our results reveal an essential role for the interferon‐inflammasome axis in cytosolic recognition and immunity against M. catarrhalis, providing new molecular targets that may be used to mitigate pathological inflammation triggered by this pathogen. Synopsis: The human respiratory pathogen Moraxella catarrhalis causes otitis media and chronic obstructive pulmonary disease. Multiple innate immune components mediate a host response against M. catarrhalis infection, including Toll‐like receptors, cGAS and STING, guanylate‐binding proteins (GBPs), and the caspase‐11‐NLRP3 inflammasome. M. catarrhalis and its secreted outer membrane vesicles deliver lipooligosaccharide (LOS) to activate the caspase‐11‐NLRP3 inflammasome.GBP1, GBP2, GBP3 and GBP5 (but not GBP4, GBP7, GBP8, GBP9 and GBP11) contribute to M. catarrhalis‐induced inflammasome activation by targeting intracellular bacteria.GBP recruitment to M. catarrhalis is independent of LOS, but GBPs facilitate membrane disruption and bacteriolysis to promote LOS release.The caspase‐11‐NLRP3 inflammasome and GBPs contribute to host defence against systemic M. catarrhalis infection. [ABSTRACT FROM AUTHOR]