CCL5/
RANTES is a key proinflammatory
chemokine produced by virus-infected epithelial cells and present in respiratory secretions of asthmatics. To examine the role of CCL5 in viral
lung disease, we measured its production during primary respiratory syncytial virus (
RSV) infection and during
secondary infection after sensitizing vaccination that induces Th2-mediated
eosinophilia. A first peak of CCL5
mRNA and
protein production was seen at 18 to 24 h of
RSV infection, before significant lymphocyte recruitment occurred. Treatment in vivo with
Met-RANTES (a competitive
chemokine receptor blocker) throughout primary
infection decreased CD4+ and CD8+ cell recruitment and increased viral replication. In RSV-infected, sensitized mice with eosinophilic disease, CCL5 production was further augmented;
Met-RANTES treatment again reduced inflammatory cell recruitment and local
cytokine production. A second wave of CCL5 production occurred on day 7, attributable to newly recruited T cells. Paradoxically, mice treated with
Met-RANTES during primary
infection demonstrated increased cellular infiltration during
reinfection. We therefore show that RSV induces CCL5 production in the lung and this causes the recruitment of RSV-specific cells, including those making additional CCL5. If this action is blocked with
Met-RANTES,
inflammation decreases and viral clearance is delayed. However, the exact effects of
chemokine modulation depend critically on time of administration,
a factor that may potentially complicate the use of
chemokine blockers in inflammatory diseases.