Cytokine-mediated neurologic disease in COVID-19

PROJECT SUMMARY The newly emerged coronavirus, SARS-CoV-2, has caused a historic pandemic of respiratory disease (COVID- 19). One surprising finding, is that both mild and severe COVID-19 is associated with persistent neurological symptoms, even after resolution of infection. Patients present with a variety of symptoms, from deficits in attention, planning, and other executive functions, to memory impairment, or new psychoses. Post-mortem analyses of brains from individuals with COVID-19 did not find evidence of infectious SARS-CoV-2 in the parenchyma. However, COVID-19 infection is associated with an array of neurological injury, including infarcts, ischemia, hemorrhages, and hypoxia. Immunohistochemistry on post-mortem specimens demonstrated that SARS-CoV-2 infection is associated with blood-brain barrier (BBB) disruption, elevated levels of the pro- inflammatory cytokine, IL-1β, and microglial activation and nodules, and neuronophagia. In other neurovirulent viral infections, IL-1β promotes inflammation in the central nervous system via disruption of the blood-brain barrier and recruitment of immune cells that activate microglia, which eliminate synapses in the hippocampus, a brain region critical for learning and memory. During recovery, IL-1β inhibits neurogenesis, which limits synapse recovery, and induces spatial memory defects. We hypothesize that IL-1β production in the brain during SARS- CoV-2 infection potentiates neurological dysfunction by disrupting the BBB and promoting cognitive and memory deficits. To investigate this, we will use a C57Bl/6 mouse model of COVID-19, in which mice are intranasally infected with B.1.351 (Beta variant), which naturally infects mice. In Aim 1, we will investigate the role of IL-1R1 signaling on BBB disruption using a brain microvascular endothelial cell (BMEC) specific inducible Cre crossed to IL-1R floxed mice. We will also determine if IL-1R1 signaling promotes activation of BMECs and the induction of inflammation. In Aim 2, we will explore if IL-1R1 signaling impacts cognition and memory via inhibition of neurogenesis within ongoing synapse elimination. First, we will determine the impact of IL-1R1 on neurogenesis during infection with B.1.351 using neural stem cell (NSC) specific, inducible Cre mice crossed to IL-1R floxed mice. Next, we test the role of IL-1R1 signaling on recovery of the hippocampal trisynaptic cirucuit via NSC- specific or microglial-specific Cre-IL-1R1 floxed mice. Last, using the same mice as the previous experiment, we will perform behavioral tests on mice recovered from B.1.351 to examine the functional impact of IL-1R1 signaling. Together, in this proposal we will explore the immunological mechanisms that underlie neurological dysfunction during COVID-19.