Project Summary/Abstract Inflammation is a pervasive contributor to the neuronal damage and cognitive decline of the normal aged brain. The low-grade, sterile inflammation of senescent cells, known as inflammageing, in the brain can be further exacerbated by extrinsic insults, such as severe infections. Due to coronavirus disease (COVID)-19 disproportionately affecting older individuals, emerging clinical data indicate that patients suffering from neurological post-acute sequalae of COVID-19 (neuro-PASC) also have a markedly higher risk of being diagnosed with Alzheimer's disease and dementia compared to age-matched healthy patients and patients recovering from a non-COVID-19 respiratory infection2,4. This clinical data is consistent with the recent findings that neuro-PASC patients have reduced gray matter thickness in their parahippocampal gyrus5. In line with this notion, this proposal is built upon preliminary data indicating that a robust hyper-phagocytic microglia response exists in the hippocampus of aged wild-type mice, but not young adult mice, inoculated with a mouse-adapted SARS-CoV-2 strain. Many of these hyper-phagocytic microglia cluster together to form `nodules', which are common in the post-mortem brains of COVID-19 patients6,7,8. No detection of SARS-CoV-2 nucleocapsid or fibrinogen in the brain parenchyma suggests that alterations in hippocampal microglia activity could be a consequence of systemic inflammation in the host. In Aim 1, the aged mouse hippocampus from mock-infected and SARS-CoV-2-infected mice will be searched for additional markers of phagocytosis as well as antigen presentation that are frequently observed in the post-mortem brains of COVID-19 patients. In addition, spatial transcriptomic data will be collected from the hippocampus to illuminate intrinsic mechanisms and cell-to-cell crosstalk that are promoting the hyper-phagocytic microglia transcriptomic signature. With early evidence that C-type Lectin domain family 7 member A (CLEC7A) is elevated on hyper-phagocytic microglia during SARS- CoV-2 respiratory infection, Aim 2 is designed to assess whether loss of spleen tyrosine kinase (SYK), a critical regulator of microglial phagocytosis and downstream effector of CLEC7A, yields homeostatic microglia activity and suppresses the synapse elimination that frequently accompanies hyper-phagocytic microglial activity in mouse models of systemic inflammation13. Collectively, this proposed project will shed light on the mechanisms behind the age-dependent emergence of hyper-phagocytic microglia and their role in the hippocampus during SARS-CoV-2 respiratory infection.

Project Narrative Since its emergence in 2019, SARS-CoV-2, a novel sarbecoronavirus, has infected at least half of the United States population and has left many individuals with debilitating neurological post-acute COVID-19 sequalae (neuro-PASC). Currently, the etiology of neuro-PASC remains unknown, but early clinical data suggests that neuro-PASC could be attributed to an overactive immune system. Therefore, in line with these recent findings, this proposed research project will determine whether microglia, the resident macrophages in the brain, rely upon the spleen tyrosine kinase (SYK) gene, an important regulator of microglia inflammatory responses, to perform pervasive activity in the COVID-19 brain.