GBP1 promotes killing of multidrug-resistantAcinetobacter baumanniiand promotes host protection via interferon signalling and inflammasome activation

Abstract

AbstractMultidrug resistant (MDR)Acinetobacter baumanniiare of major concern worldwide due to their resistance to last resort carbapenem and polymyxin antibiotics. To develop an effective treatment strategy, it is critical to better understand how anA. baumanniiMDR bacterium interacts with its mammalian host. Pattern-recognition receptors sense microbes, and activate the inflammasome pathway, leading to pro-inflammatory cytokine production and programmed cell death. Here, we found that MDRA. baumanniiactivate the NLRP3 inflammasome complex predominantly via the non-canonical caspase-11-dependent pathway. We show that caspase-11-deficient mice are protected from a virulent MDRA. baumanniistrain by maintaining a balance between protective and deleterious inflammation via IL-1. Caspase-11-deficient mice also compromise between effector cell recruitment, phagocytosis, and programmed cell death in the lung during infection. Importantly, we found that cytosolic immunity - mediated by guanylate-binding protein 1 (GBP1) and type I interferon signalling - orchestrates caspase-11-dependent inflammasome activation. This exerts a bactericidal activity against carbapenem- and colistin-resistant, lipooligosaccharide (LOS)- deficient bacteria. Together, our results suggest that developing therapeutic strategies targeting GBP1 might pave the way as a host-directed therapy to overcome multidrug resistance inA. baumanniiinfection.