Age-related differences in pulmonary cytokine response to respiratory syncytial virus infection: modulation by anti-inflammatory and antiviral treatment.

BACKGROUND: Respiratory syncytial virus (RSV) is the major cause of severe lower respiratory tract infection in infants and young children. Recently, RSV has also been recognized as a serious health risk in elderly individuals, but the pathogenesis of RSV infection in elderly individuals remains unknown. METHODS: Dynamics of pulmonary cytokine response (including interferon- gamma , interleukin [IL]-4, IL-10, IL-6, monocyte chemoattractant protein-1, and growth-regulated oncogene [GRO] mRNA) during acute RSV infection were investigated in young (<2 months old) and aged (>9 months old) cotton rats (Sigmodon hispidus). Therapeutic treatments that diminish viral replication (antiviral antibody) and pulmonary inflammation (anti-inflammatory corticosteroid) in RSV-infected cotton rats were used to evaluate the contribution of virus replication and inflammation to the development of RSV disease with respect to age. RESULTS: The time of the peak expression of the majority of cytokines was shifted with respect to age. Antiviral and anti-inflammatory treatments had a similar effect on cytokine expression in aged and young cotton rats. GRO mRNA transcripts were more abundant in the lungs of aged cotton rats. CONCLUSIONS: The present study reports an age-related delay in the pulmonary cytokine response to RSV and an imbalance in chemokine production with respect to age and underscores different components of RSV pathogenesis with respect to their molecular signature.

Pathogenesis of human metapneumovirus lung infection in BALB/c mice and cotton rats.

Human metapneumovirus (hMPV) is a newly described member of the Paramyxoviridae family causing acute respiratory tract infections, especially in young children. We studied the pathogenesis of this viral infection in two experimental small animal models (BALB/c mice and cotton rats). Significant viral replication in the lungs of both animals was found following an intranasal challenge of 10(8) 50% tissue culture infectious doses (TCID50) and persisted for <2 and <3 weeks in the case of cotton rats and mice, respectively. Peak viral loads were found on day 5 postinfection in both mice (mean of 1.92 x 10(7) TCID50/g lung) and cotton rats (mean of 1.03 x 10(5) TCID50/g). Clinical symptoms consisting of breathing difficulties, ruffled fur, and weight loss were noted in mice only around the time of peak viral replication. Most significant pulmonary inflammatory changes and peak expression of macrophage inflammatory protein 1alpha, gamma interferon, and RANTES occurred at the time of maximal viral replication (day 5) in both models. Cellular infiltration occurred predominantly around and within alveoli and persisted for at least 21 days in mice, whereas it was more limited in time with more peribronchiolitis in cotton rats. Both animal models would be of great value in evaluating different therapeutic agents, as well as vaccine candidates against hMPV.