Prostaglandin D2 delays CD8+ T-cell responses and respiratory syncytial virus clearance in geriatric cotton rats.

Respiratory syncytial virus (RSV) infection is associated with increased rates of severe disease, hospitalization, and death in elderly individuals. Clearance of RSV is frequently delayed within this demographic, contributing to the more severe disease course. Geriatric cotton rats mimic this prolonged clearance kinetic and serve as a useful animal model for studying age-associated immunological deficits during RSV infection. Treatment with the cyclooxygenase (COX) inhibitor ibuprofen restores RSV clearance, indicating that inflammation contributes to impaired clearance in geriatric cotton rats. Here, we further characterize a compromised immune response in geriatric cotton rats and identify an inflammatory pathway that contributes to this deficiency. Dendritic cell (DC) activation and migration to mediastinal lymph nodes are decreased during early infection in geriatric cotton rats, resulting in delayed generation of cytotoxic T cells and virus clearance. Prostaglandin D₂ (PGD2), which reduces DC migration through the elevation of D-type prostanoid 1 receptor (DP1 receptor), is elevated in the airways of infected geriatric cotton rats. Reducing PGD2 production by inhibiting COX-2 or PGD2 synthase improves RSV clearance kinetics through DC activation and RSV-specific CD8+ T-cell responses in geriatric cotton rats, whereas activation of DP1 receptor through an agonist resulted in delayed viral clearance in adult cotton rats. These results indicate that PGD2 contributes to delayed antigen presentation and CD8+ T-cell responses to RSV in geriatric cotton rats. Inhibiting PGD2 generation or signaling may be a useful mechanism of therapeutic intervention in elderly individuals.IMPORTANCEElderly adults are at increased risk of severe disease resulting from infection with respiratory syncytial virus (RSV), characterized in part by delayed clearance (removal of the virus from airways). Understanding the immunological factors that lead to this delayed clearance may allow for the development of therapies to improve disease outcomes in elderly individuals infected with RSV and other respiratory viruses. Here, we describe an inflammatory pathway in geriatric cotton rats, the preferred small animal laboratory model for RSV, that impairs the generation of an effective immune response. We show that inhibiting this inflammatory pathway in geriatric cotton rats improves immune parameters and speeds clearance of RSV. These results contribute to our understanding of delayed RSV clearance in elderly individuals with possible applications for improving immune responses to RSV in clinical settings.