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Acute and Chronic Airway Responses to Viral Infection

Implications for Asthma and Chronic Obstructive Pulmonary Disease

Pulmonary and Critical Care Medicine, Department of Medicine; and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Correspondence and requests for reprints should be addressed to M. J. Holtzman, M.D., Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: holtzman{at}im.wustl.edu

Despite the high clinical impact of established and emerging respiratory viruses, some critical aspects of the host response to these pathogens still need to be defined. In that context, we aimed at two major issues: first, what are the innate immune mechanisms that control common respiratory viral infections; and second, whether these mechanisms also cause long-term airway disease. Using a mouse model of viral bronchiolitis, we found that antiviral defense depends at least in part on a network of mucosal epithelial cells and macrophages specially programmed for immune-response gene expression. When this network is compromised, the host is highly susceptible to infection, but network components can be engineered to provide increased resistance to infection. Similar alterations appear in asthma and chronic bronchitis/chronic obstructive pulmonary disease, suggesting that evolving attempts to improve antiviral defense may also lead to inflammatory airway disease. Indeed, in genetically susceptible mice, respiratory paramyxoviruses cause a "hit and run" phenomenon that is manifested by the development of a permanent airway disease phenotype long after the infection has cleared. The phenotype can be segregated into individual traits to achieve more precise definition of just how viruses reprogram host behavior. Identifying specific components of the mucosal immune system that manifest an aberrant antiviral response may thereby allow for adjusting this response to improve acute and chronic outcomes after viral infection.

Key Words: airway hyperreactivity • apoptosis • chemokine • interferon signal transduction • mucosal immunity • mucous cell metaplasia

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