Clinical and experimental observations suggest that chronic lung disease is linked to respiratory viral infection. However, the long-term aspect of this relationship is not yet defined using a virus that replicates at properly high levels in humans and a corresponding animal model. In this study, we show that influenza A virus infection achieves 1 × 10-fold increases in viral load in the lung and dose-dependent severity of acute illness in mice. Moreover, these events are followed by persistence of negative- and positive-strand viral RNA remnants for 15 wk and chronic lung disease for at least 26 wk postinfection. The disease is manifested by focal areas of bronchiolization and mucus production that contain increased levels of viral RNA remnants along with mucin Muc5ac and Il13 mRNA compared with uninvolved areas of the lung. Excess mucus production and associated airway hyperreactivity (but not fibrosis or emphysema) are partially attenuated with loss of IL-13 production or signaling (using mice with IL-13 or STAT6 deficiency). These deficiencies cause reciprocal increases in l17a mRNA and neutrophils in the lung; however, none of these disease endpoints are changed with IL-13/IL-17a compared with IL-13 deficiency or STAT6/IL-17a compared with STAT6 deficiency. The results establish the capacity of a potent human respiratory virus to produce chronic lung disease focally at sites of active viral RNA remnants, likely reflecting locations of viral replication that reprogram the region. Viral dose dependency of disease also implicates high-level viral replication and severity of acute infection as determinants of chronic lung diseases such as asthma and COPD with IL-13-dependent and IL-13/IL-17-independent mechanisms.

Background Pre-existing antibodies to influenza, shaped by early infection and subsequent exposures, may impact responses to influenza vaccination. Methods We enrolled 72 children (7-17 years) in 2015-16, all received inactivated influenza vaccines. Forty-one were also vaccinated in 2014-15 with 12 became infected with A(H3N2) in 2014-15. Thirty-one children did not have documented influenza exposures in the prior 5 seasons. Sera were collected pre- and post-vaccination in both seasons. We constructed antibody landscapes using hemagglutination inhibition antibody titers against 16 A(H3N2) viruses representative of major antigenic clusters that circulated between 1968 and 2015. Results The breadth of the antibody landscapes increased with age. Vaccine-induced antibody responses correlated with boosting of titers to previously encountered antigens. Post-vaccination titers were highest against vaccine antigens rather than the historic A(H3N2) viruses previously encountered. Pre-vaccination titers to the vaccine were the strongest predictors of post-vaccination titers. Responses to vaccine antigens did not differ by likely priming virus. Influenza A(H3N2) infected children in 2014-15 had narrower antibody landscapes than those uninfected, but prior season infection status had little effect on antibody landscapes following 2015-16 vaccination. Conclusions A(H3N2) antibody landscapes in children were largely determined by age-related immune priming, rather than recent vaccination or infection.

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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.

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