Antigen non-specific CD8⁺ T cells accelerate cognitive decline in aged mice following respiratory coronavirus...

Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed "long COVID". Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8⁺ T cells within the brains of aged animals but reduced antigen specificity of those CD8⁺ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8⁺ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8⁺ T cell-derived IFN-γ correlated with neuronal death. These results support the evidence that CD8⁺ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals.