The pandemic matrix gene is associated with increased pro-inflammatory immune responses during influenza virus infection

Abstract

Abstract The 2009 H1N1 influenza pandemic (pdmH1N1) arose from multiple genetic reassortment events between three swine influenza A virus (swIAV) lineages and became established as a seasonal H1N1 human influenza virus. Through reverse-zoonotic events, the pdmH1N1 strain contributed gene segments to endemic swIAVs and the pandemic matrix gene (pdmM) completely replaced the classical swine matrix gene (swM), suggesting a fitness benefit. We assessed a panel of swIAVs in the BALB/c mouse model and demonstrated that swIAVs containing the pdmM gene caused increased morbidity, lung pathology, and mortality compared to swIAVs containing the swM gene. We hypothesized that swIAVs containing the pdmM gene induce dysregulation of the innate response, causing increased disease. To test this, mice were infected with swIAVs containing either the pdmM or the swM gene segment, and immune cell infiltrates, cytokine production, and histopathology were assessed. We found that pdmM viruses elicited increased cellular infiltration, NK cell activation and increased IFNγ production in bronchial alveolar lavage (BAL) fluid compared to mice infected with swM viruses. We also detected increased numbers of infiltrating macrophages, neutrophils, DCs, and eosinophils, as well as increased proinflammatory cytokine production. Additionally, elevated myeloperoxidase content was detected in BAL fluid, suggesting increased neutrophil activation. Finally, infection with pdmM viruses resulted in greater histologic lesion scores compared to swM viruses. We conclude the pdmM gene elicits increased innate immune responses, causing greater disease in a mouse model of infection. Future studies will identify determinants of increased disease severity.