VIRAL INDUCTION OF A CHRONIC ASTHMA PHENOTYPE AND GENETIC SEGREGATION FROM THE ACUTE RESPONSE

Abstract

Walter MJ, Morton JD, Kajiwara N, Agapov E, Holtzman MJ. J Clin Invest. 2002;110:165–175To address the role of persistent infection and cytokine bias in the development of the chronic asthma phenotype after paramyxoviral infection.The investigators used a mouse model of paramyxoviral bronchiolitis with acute pathology similar to the human condition. Wild-type C57BL/6J, same-strain interferon gamma (IFN-γ)-null mice and same-strain intercellular adhesion molecule-1 (ICAM-1)-null mice were maintained under pathogen-free conditions for study at 7 to 9 weeks of age. Mice were inoculated with mouse parainfluenza virus type 1 (Sendai virus; SeV Fushimi strain) or ultraviolet (UV)-inactivated SeV. Histochemistry of the mouse lung, bronchoalveolar lavage fluid analysis, and airway reactivity measurements to aerosolized methacholine were performed. In addition, allergen challenges were performed with ovalbumin using sensitized and nonsensitized C57BL/6J mice.Following a single paramyxoviral infection of mice (C57BL6/J strain), the investigators demonstrate that not only does this produce acute bronchiolitis, but also a chronic lung response with airway hyperreactivity and goblet cell hyperplasia lasting at least 1 year after complete viral clearance. During the acute response to virus, same-strain ICAM-1-null mice are protected from airway inflammation and hyperreactivity despite similar viral infections rates; however, the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-γ deficiency, but the chronic response is at least partially prevented by glucocorticoid treatment. In contrast to viral infection, allergen challenge caused only short-term expression of asthma phenotypes.Paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes. These 2 phenotypes can be segregated by their dependence on the ICAM-1 gene and so depend on distinct controls that appear critical for the development of lifelong airway diseases such as asthma. These findings raise the possibility that asthma not only resembles a persistent antiviral response, but also may be caused by such a response. These data may help provide a link between paramyxoviral infections in infancy with subsequent asthma in later in life.This is a very provocative study that strikes at the core of the ongoing debate regarding the specific role of acute viral lower respiratory tract illnesses and the predisposition to chronic asthma. Previous investigations have demonstrated that paramyxoviral infections and asthma may activate a network of epithelial immune-response genes that are part of the innate immune response. The current investigation provides strong evidence to support this concept and provides new insight into how paramyxoviral infections may lead to chronic airway changes in structure and function, which are typical of asthma. Additional studies will be needed to identify the genes responsible for epithelial remodeling and chronic hyperreactivity in response to this type of viral infection. Furthermore, additional investigation will be needed to confirm and further elucidate this type of a viral pathway, which is distinct from an allergen-driven pathway that may lead to chronic airway dysfunction manifested in asthma.