Influenza A virus infection causes chronic lung disease linked to IL-13 and mucin expression at sites of viral remnants

Abstract

Abstract Clinical and experimental observations suggest that the development of chronic obstructive lung disease is linked to respiratory viral infection. However, there is no experimental model that establishes the long-term aspect of this relationship using a human pathogen with high level viral replication. Here we show that influenza A virus (IAV) infection achieves million-fold increases in viral load in the lung and dose-dependent severity of acute illness followed by long-term persistence of negative and positive strand viral remnants and similarly dose-dependent development of chronic lung disease. The disease persists for at least 6 months and is manifested by focal areas of bronchiolization and mucus production that contain increased levels of IAV remnants along with mucin Muc5ac and Il13 mRNA expression. These disease manifestations and airway hyper-reactivity are attenuated with loss of IL-13 production or signaling (using Il13 or Stat6 deficient mice). These deficiencies also cause reciprocal increases in l17a mRNA and neutrophils in the lung, however, post-viral mucus production and hyper-reactivity are unchanged with combined IL-13–IL-17a deficiency compared to IL-13 deficiency or with STAT6-IL-17a deficiency compared to STAT6 deficiency. The results establish the capacity of a potent human respiratory virus to produce chronic lung disease at sites of viral remnants, presumably reflecting locations of viral replication that eventually translate to IL-13-driven mucus production. Since highly infectious mouse parainfluenza virus causes similar disease, the findings also implicate high-level viral replication and severity of infection as key determinants of hyper-secretory lung diseases such as asthma and COPD.