Nrf2 regulates host defense against carbapenem-resistant Klebsiella pneumoniae pneumonia through leukocyte homeostasis and function 2592

Abstract Description Rationale The role of Nrf2 in host defense against carbapenem-resistant Klebsiella pneumoniae (CRKP) (aka superbug) remains elusive. Methods We conducted intracellular and extracellular bacterial killing assays using bone marrow-derived macrophages (BMDMs) and neutrophils (BMDNs) from wild type (WT) and Nrf2 knock out (Nrf2 KO) mice. We infected the WT and Nrf2 KO mice with CRKP and sacrificed the mice 48 h post-infection. We assessed bacterial burden in pulmonary and distal organs, performed bronchoalveolar lavage (BAL) phenotyping, analyzed lung pathology, examined emergency granulopoiesis, measured cytokines in BAL fluids (BALF) and monitored survival after infection with CRKP. Results Nrf2 was found to be upregulated in human and WT mouse pneumonic lungs. WT BMDMs are more potent in the phagocytosis and intracellular killing of opsonized CRKP than KO BMDMs although both WT and KO BMDNs are inefficient in extracellular killing. Also, KO BMDNs exhibit reduced NETosis after infection. Furthermore, KO mice infected with CRKP show augmented neutrophil and macrophage recruitment, production of inflammatory cytokines (TNFα and IL-1β) in BALF, lung pathology, pulmonary fibrosis, bacterial burden in the lungs and distal organs, and mortality. Moreover, KO mice display impaired emergency granulopoiesis after infection. Conclusions Nrf2 is critical to host defense against CRKP pneumonia by modulating leukocyte homeostasis and function. Funding Sources Supported by NIH grants (R01AI157353, R01A1180123, 1RO1AI140500-01, 1P20GM130555-01, 1P20GM130555-06, 1R21AI133681-01A1) Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)