Mechanisms of T cell-mediated cognitive impairment during SARS-CoV-2 infection

Many individuals who recover from COVID-19 experience long-term symptoms affecting the brain, such as memory problems, difficulty concentrating ("brain fog"), anxiety, and chronic headaches, referred to as post-acute neurological symptoms of COVID-19 (neuroPASC). However, the mechanisms leading to neuroPASC remain unclear, limiting the development of effective treatments. Emerging evidence suggests that inflammation in the brain, rather than direct viral infection, may be responsible for these symptoms. Interestingly, several studies have shown higher numbers of immune cells called T cells in the brains of mice and humans following SARS-CoV-2 infection, even though the virus does not infect the brain. While T cells can help protect against future infections, they may also contribute to neuroinflammation and detrimental immune activation in the brain. Using a model of SARS-CoV-2 infection that replicates neuroPASC, we aim to determine whether T cells residing in the brain long-term influence other brain immune cells, called microglia, impair neurogenesis (the formation of new neurons), and contribute to memory deficits following SARS-CoV-2 infection. To test this, we will compare normal mice with mice that lack key factors necessary for T cells to reside in the brain long-term to identify the contribution of these cells to cognitive decline. Additionally, viral infections and T cell-driven neuroinflammation have been linked to development of neurodegenerative diseases, such as Alzheimer's disease (AD), but it is unknown if COVID-19 may accelerate AD progression. Using a mouse model of AD, we will investigate the impact of SARS-CoV-2 infection and T cells in the brain on memory impairments and AD progression, providing new insights into long-term consequences of viral infections.