Exploring the role of hyper-phagocytic microglia and SYK signaling in the aged hippocampus during COVID-19

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.