Investigating the role of T cells in promoting post-acute memory deficits after COVID-19 in mice - Project Summary Millions of individuals in the United States suffer from post-acute symptoms of COVID-19 (PASC), many of which are neurological in origin. Although SARS-CoV-2 does not cause widespread infection of the central nervous system (CNS), significant neuroinflammation, decreased adult neurogenesis, alterations in synaptic proteins, decreased total brain volume, and poor performance on tests of learning and memory have all been observed in COVID-19 patients. However, the mechanisms by which a respiratory virus is causing persistent neurological dysfunction are not well understood. Studies of PASC patients identified ongoing dysregulation of T cell responses in the serum and imaging studies confirmed that PASC patients have activated T cells in the CNS. Homeostatic T cells in the meninges are known to influence learning, memory, and anxiety-like behavior through the secretion of cytokines, however the impact of T cells on neurological symptoms after COVID-19 is unknown. Thus, I hypothesize that systemic inflammation promotes recruitment of antigen-specific T cells to the CNS after SARS-CoV-2 infection, and these cells contribute to persistent deficits in learning and memory via secretion of cytokines and other pro-inflammatory mediators. To investigate this, I will utilize my recently developed mouse model of neurological dysfunction after COVID-19, in which intranasal infection of wild-type mice with SARS-CoV-2 causes robust infection of the respiratory tract, but not the CNS, post-acute memory deficits, loss of hippocampal neurogenesis, and increased pro-inflammatory cytokines in the CNS. Preliminary data found that CD4+ T cells are recruited to the meningeal dura after infection and promote post-acute memory deficits as determined via the Novel Object recognition test. In the K99 phase of this proposal, (Aim 1) I will investigate the phenotype of CD4+ T cells in the CNS after SARS-CoV-2 infection and determine how cytokines secreted by CD4+ T cells may contribute to memory deficits using a behavioral test battery and investigation of neurogenesis and tri-synaptic circuit function. In Aim 2, I will test if T cell priming and differentiation impact pathogenicity in the CNS after COVID-19 by first, determining if antigen specificity is required for recruitment to and effector functions in the CNS and second, investigating which CD4+ T cell effector subset is driving post-acute memory deficits. In the R00 phase, I will utilize a previously established murine model of breakthrough vaccination to investigate how priming of CD4+ T cells in the periphery influences differentiation into a pathogenic CD4+ effector subset. In Aim 3, I will explore how severe, systemic inflammation may be driving recruitment of these pathogenic T cells to the CNS and which chemokine: receptor pairs are critical for this process. Combined, this project will determine the mechanisms by which pathogenic CD4+ T cells are recruited to the CNS after COVID-19 and how they promote post-acute learning and memory deficits. These data could identify fundamental mechanisms by which immunity to viral infections controls neurological function and potential druggable targets for treatment of PASC.