Influenza Virus Infection Increases Host Susceptibility To Secondary Infection with Pseudomonas aeruginosa, and This Is Attributed To Neutrophil Dysfunction through Reduced Myeloperoxidase Activity

Abstract

Secondary bacterial infection greatly increased the morbidity and mortality of influenza virus infection. To investigate the underlying mechanism by which influenza impairs the pulmonary defense against secondary Pseudomonas aeruginosa ( P. aeruginosa ) infection, we established a lethal mouse model in which to study secondary P. aeruginosa infection after influenza virus infection. We found a significant increase in host susceptibility to a secondary infection with P. aeruginosa in mice after an influenza virus infection, and this was accompanied by severe immunopathology and pulmonary inflammation. Importantly, we demonstrated that neutrophils were essential for P. aeruginosa clearance in secondarily infected mice. Further, we revealed that influenza impaired the phagocytosis and digestion functions of pulmonary neutrophils for P. aeruginosa clearance. We identified that the activity of reactive oxygen species (ROS) and the myeloperoxidase (MPO) activity of neutrophils in the lungs played an important role in antibacterial host defense in influenza-infected lungs. Hereby, influenza virus infection causes deficient MPO activity in neutrophils, and this contributes to the increased susceptibility to secondary P. aeruginosa infection. Treatment with Bacillus Calmette-Guerin polysaccharide nucleic acid (BCG-PSN) prior to secondary P. aeruginosa infection may improve the function of neutrophils, resulting in significantly reduced lethality during secondary P. aeruginosa infection. We also demonstrated that treatment with anti-influenza immune serum during the early stage of an influenza virus infection could decrease the disease severity of secondary P. aeruginosa infection. Our findings suggest that improving the MPO activity of neutrophils may provide a therapeutic strategy for viral-bacterial coinfection. IMPORTANCE A secondary bacterial infection, such as that of P. aeruginosa , often occurs after a pulmonary virus infection and contributes to severe disease. However, the underlying mechanisms responsible for viral-bacterial synergy in the lung remain largely unknown. In this study, we reported that influenza virus infection increases a host’s susceptibility to secondary infection by P. aeruginosa by reducing the MPO activity of neutrophils. We also demonstrated that treatment with BCG-PSN or anti-influenza immune serum prior to secondary P. aeruginosa infection can reduce the disease severity. Our findings suggest that improving the MPO activity of neutrophils may provide a therapeutic strategy for viral-bacterial coinfection.