Mitochondrial antiviral signalling protein (MAVS) triggers innate immunity against bacterial lung infection

<bold>Introduction</bold> Mitochondrial antiviral signalling protein (MAVS) is an intracellular pathogen recognition receptor for viruses, inducing type I/III IFN and activating NFκB and IRF3. MAVS polymorphisms are associated with asthma in children. Azithromycin is an effective therapy for asthma exacerbations through unknown mechanisms. Non-typeable Haemophilus influenzae (NTHI) is the dominant pathogen in the human airways. <bold>Material and Methods</bold> We infected C57BL/6 (wt) and MAVS KO mice with NTHi and analysed bacterial loads, weight loss, pathological change of lung tissues, infection progression, inflammatory and immune responses by transcriptomics and spectral flow cytometry. Further studies were performed <italic>in vitro</italic> on airway epithelial cells. <bold>Results</bold> NTHI infection decreased pulmonary MAVS mRNA and protein. At 24 h pulmonary bacterial loads were higher in MAVS KO than in wt mice, whilst wt mice suffered more weight loss, suggesting MAVS is required for early, protective immune activation. RIG-I and MDA5 activation were not affected. NTHi significantly reduced type I/III IFN production in wt mice and MAVS KO mice. MAVS KO mice showed a weaker induction of IFN-β in lung homogenate. MAVS KO mice showed a significantly lower/slower inflammatory response during NTHI infection than wt mice. The immune cells profile of MAVS KO mice is distinct from the wt mice during infection. <italic>In vitro</italic> MAVS binds to azithromycin which can respond deficient IFN-β in NTHi coinfection. <bold>Conclusions</bold> MAVS plays an important role in innate immunity against bacterial lung infection, is targeted by NTHi for immune evasion, but is restored by azithromycin.