Age-dependent differences in the immune response to human metapneumovirus

Abstract

Abstract Objective: Human metapneumovirus (HMPV) is a leading cause of serious respiratory infection in older adults, but pathophysiology in this population is incompletely understood. Methods: We developed an elderly mouse model of HMPV using 72-week-old mice. Aged mice and 6-week-old mice were infected intratracheally with HMPV and euthanized at different time points to measure viral titer and cellular immune response. We also infected young v. aged macrophages in vitro to determine cytokine response. Results: Aged HMPV-infected mice demonstrated increased weight loss, higher clinical disease scores, increased lung histopathology, and delayed viral clearance with virus persisting in the lung through day 9 post-infection while 6-week young mice cleared infection completely by day 7. Aged mice showed a significant increase in absolute number of CD8+ T cells in bronchoalveolar lavage (BAL) and lung; however, CD8+ T cells in aged mice exhibited fewer HMPV-specific tetramer+ CD8+ cells in both BAL and lung. Most aged cells expressed two or more impairment receptors (PD1, LAG3, or TIM3). Luminex analysis of lung homogenate and BAL revealed increased Th2 and inflammatory cytokine expression in aged mice. Aged HMPV-infected peritoneal macrophages in vitro had significantly increased expression of IFNb and decreased IFNg, while bone marrow-derived macrophages had decreased IFNl expression. Conclusions: These findings suggest that aged mice have a dysregulated CD8+ T cell response to HMPV, increasing disease but delaying viral clearance. Altered cytokine production by aged macrophages may skew CD8+ T cell response. Future studies will investigate the specific mechanisms surrounding impaired immune response in the aged host.