Reduced inflammatory and Th1 transcriptional profiles in geriatric versus adult cotton rats infected with respiratory syncytial virus.

Human respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in elderly populations. RSV clearance is delayed in individuals over 65 years of age, a finding that is recapitulated in the geriatric cotton rat model. Altered inflammatory responses in elderly populations have been implicated with impaired clearance of several pathogens but remain poorly described for RSV. We performed RNA sequencing (RNA-seq) and pathway analysis on lung tissue of RSV-infected adult and geriatric cotton rats to characterize differential host immune responses between these age groups. No differences in inflammatory gene expression were observed between uninfected adult and geriatric cotton rats. At day 1 post-infection, adult cotton rats expressed higher levels of genes encoding several cytokines and transcription factors associated with acute inflammation and initiation of a Th1 response, including IFN- β, IL12, and Tbet, compared to geriatric cotton rats. By day 4 post-infection, adult cotton rats additionally expressed higher levels of genes encoding effector molecules associated with Th1 responses, including IFN-γ. Pathway analysis showed significantly increased activation of several pro-inflammatory pathways in adults, including the Th1 pathway, macrophage classical (M1) activation, and pathogen-induced cytokine signaling. To evaluate lymphocyte Th1/Th2 polarization resulting from RSV infection in both age groups, we stimulated splenocytes with RSV antigen at day 28 post-infection and measured IFN-γ and IL-4 production by ELISA. Splenocytes of all adult cotton rats produced detectable IFN-γ and no IL-4, indicating Th1 polarization. Splenocytes of all geriatric cotton rats produced detectable IL-4, indicating Th2 polarization. Collectively, these results indicate that geriatric cotton rats exhibit impaired generation of a Th1 response and a decreased inflammatory response overall to RSV.