Role And Mechanism Of IL-6 In Influenza-Streptococcus Pneumoniae Coinfected Pneumonia And Pneumococcal Pneumosepsis

BACKGROUND:Pneumonia in humans has always been an important cause of illness and death.Influenza A virus（IAV）and S.pneumoniae are two main pathogens that cause human pneumonia.While,in some cases,influenza and pneumococcal pneumonia can be resolved by the immune system without major sequelae,host who fail to control invading pathogens and resolve ongoing inflammation will suffer severe pneumonia and death ensues.Interestingly,more than 95%of all severe illness and deaths in the1918 and 2009 influenza pandemics were complicated by bacterial co-infection,most of these（～50%）were S.pneumoniae infection.Inaddition,persistent pneumococcal pneumonia can cause sepsis,that is,pneumococcal pneumosepsis.High mortality and morbidity are common features of IAV-S.pneumoniae co-infected pneumonia and pneumococcal pneumosepsis,but the pathogenesis of these two S.pneumoniae-related diseases have not been fully elucidated so far.Interleukin-6（IL-6）is one of the most induced cytokines during IAV-S.pneumoniae co-infected pneumonia and pneumococcal pneumosepsis.Many studies have found that IL-6 can promote host to resist various infections,but the role of elevated IL-6 in co-infected pneumonia and the relevant mechanism of IL-6 in resisting S.pneumoniae-related infection are still unclear.Therefore,this study intends to explore the role and mechanism of IL-6 in IAV-S.pneumoniae co-infected pneumonia and pneumococcal pneumosepsis.METHODS:First,the clinically relevant co-infected and pneumosepsis mice model were established by instilling the mouse-adapted IAV（A/Puerto Rico/8/1934,PR8）and S.pneumoniae（D39）or only D39respectively through bilateral nasal cavity.The pathological characteristics of two mice model are similar to humans.Second,we explored the role of IL-6 in these two diseases.We used WT and IL-6^-/-mice to establish two different mouse models,and then observed the relevant inflammation indicators,such as,survival,virus titer,bacterial load,lung tissue pathology,cytokine and so on.Finally,we studied the relevant mechanisms of IL-6 exerted its role in these two diseases.In vivo and in vitro experiments were used to explore the mechanism of IL-6 and verify the therapeutic effect of exogenous IL-6protein.RESULTS:The clinically relevant co-infected mice and pneumosepsis mice displayed dramatically elevated IL-6.IL-6^-/-mice presented with increased bacterial burden,early dissemination of bacteria to extrapulmonary sites accompanied by aggravated pulmonary lesions and high mortality when co-infection and pneumosepsis.Importantly,therapeutic administration of recombinant IL-6 protein reduced cells death in BALF,and enhanced macrophages phagocytosis through increased MARCO expression during co-infection.We then demonstrated that IL-6contributes to S.pneumoniae-induced lung macrophages death and lung inflammation injury by inhibiting GSDME-and GSDMD-mediated pyroptosis during pneumococcal pneumosepsis.CONCLUSIONS:IL-6 plays an important protective role in host resisting the onset of IAV-S.pneumoniae co-infected pneumonia and pneumococcal pneumosepsis.IL-6 enhances the macrophage-mediated antibacterial response,which provides a unique direction for host to fight against complicated influenza pneumonia and secondary bacterial infections.This protective immune mechanism allows us to further understand the potential impact of immune molecules during infection and provides potential treatment options and approaches for S.pneumoniae-related infections.