Influenza a virus infection causes chronic lung disease linked to sites of active viral RNA remnants

Shamus P. Keeler, Eugene V. Agapov, Michael E. Hinojosa, Adam N. Letvin, Kangyun Wu, Michael J. Holtzman

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Clinical and experimental observations suggest that chronic lung disease is linked to respiratory viral infection. However, the longterm 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 × 106-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 positivestrand 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.

Original languageEnglish
Pages (from-to)2354-2368
Number of pages15
JournalJournal of Immunology
Volume201
Issue number8
DOIs
StatePublished - Oct 15 2018

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