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A guinea pig model of human respiratory syncytial virus lung infection Hegele, Richard G.


Children who have an episode of acute respiratory syncytial virus (RSV) bronchiolitis are at increased risk for developing asthma, a disorder characterized by reversible airway obstruction, airway hyperresponsiveness and airway inflammation. Because latent or persistent pulmonary viral infections have been implicated in the pathogenesis of the airway inflammation underlying asthma, a guinea pig model of human RSV lung infection was developed to test the hypothesis that RSV persists within the lung following resolution of acute bronchiolitis. One month old, "juvenile" guinea pigs, intranasally inoculated with human RSV, were compared on day 6 post-inoculation to two month old, "adolescent" RSV-inoculated animals and uninfected controls by clinical examination, gross lung examination and lung histopathological examination using a semi-quantitative scoring system for bronchiolar inflammation. The natural history of intrapulmonary RSV was studied in juvenile animals on days 6, 14, 60 and 125 using viral culture to test for replicating virus, transmission electron microscopy (TEM) to test for assembled virus, immunohistochemistry to test for RSV antigens and the reverse transcriptase-polymerase chain reaction (RT-PCR) to test for RSV genomic RNA. The experiments showed that juvenile guinea pigs inoculated with human RSV developed statistically significant bronchiolar inflammation by day 6 that resolved by day 14, similar to human acute bronchiolitis. Intrapulmonary RSV was documented by culture, TEM, immunohistochemistry and RT-PCR during acute infection on day 6; in the longer term studies, replicating RSV was cultured up to 14 days post-inoculation, RSV antigens were identified within alveolar macrophages up to day 60 and RSV genomic RNA was identified on day 125. In conclusion, human RSV produced a self-limited acute bronchiolitis in juvenile guinea pigs, with evidence of subsequent persistent infection of alveolar macrophages. Persistent RSV infection of alveolar macrophages may represent a mechanism by which host pulmonary defense mechanisms are compromised against other, non-specific environmental agents implicated in the pathogenesis of asthma.

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