Inducible expression of inflammatory chemokines in respiratory syncytial virus-infected mice: Role of MIP-1 alpha in lung pathology

Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants w ith naturally acquired infection and in experimentally inoculated animal mo dels. Chemokines are central regulatory molecules in inflammatory immune, a nd infectious processes of the lung. In this study, we demonstrate that int ranasal infection of BALB/c mice,vith RSV A results in inducible expression of lung chemokines belonging to the CXC (MIP-2 and IP-10), CC (RANTES, eot axin, MIP-1 beta, MIP-1 alpha, MCP-1, TCA-3) and C (lymphotactin) families. Chemokine mRNA expression occurred as early as 24 h following inoculation and persisted for at least 5 days in mice inoculated with the highest dose of virus (10(7) PFU). In general, levels of chemokine mRNA and protein were dependent on the dose of RSV inoculum and paralleled the intensity of lung cellular inflammation. Immunohisthochemical studies indicated that RSV-ind uced expression of MIP-1 alpha, one of the most abundantly expressed chemok ines, was primarily localized in epithelial cells of the alveoli and bronch ioles, as well as in adjoining capillary endothelium, Genetically altered m ice with a selective deletion of the MIP-1 alpha gene (-/- mice) demonstrat ed a significant reduction in lung inflammation following RSV infection, co mpared to control littermates (+/+ mice). Despite the paucity of infiltrati ng cells, the peak RSV titer in the lung of -/- mice was not significantly different from that observed in +/+ mice. These results provide the first d irect evidence that RSV infection may induce lung inflammation via the earl y production of inflammatory chemokines.