Viral induction of a chronic asthma phenotype and genetic segregation from the acute response.
Paramyxoviral infections cause most of the acute lower respiratory tract illness in infants and young children and predispose to the development of chronic wheezing, but the relationship between these short- and long-term viral effects are uncertain. Here we show that a single paramyxoviral infection of mice (C57BL6/J strain) not only produces acute bronchiolitis, but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a 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 infection rates, but the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-gamma 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. Thus, paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-run strategy, since viral effects persist after clearance). These two 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.
Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Michael J
MJ
Walter
Jeffrey D
JD
Morton
Naohiro
N
Kajiwara
Eugene
E
Agapov
Michael J
MJ
Holtzman
D000208:Acute Disease; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001988:Bronchiolitis / Q000150:complications; D002675:Child, Preschool; D002908:Chronic Disease; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007223:Infant; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012130:Respiratory Hypersensitivity / Q000209:etiology; D010253:Respirovirus Infections / Q000150:complications*; D029082:Sendai virus / Q000472:pathogenicity
D000485:Allergens; D005938:Glucocorticoids; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone