Viral and immune-mediated CNS pathology during SARS-CoV-2 infection

Project SummaryThe COVID-19 pandemic has rampantly affected the population of the world and created lasting effects on theeconomy, health and psyche of the global community. Although it shares similarities with SARS-CoV-1, the fullextent of the pathophysiology caused by SARS-CoV-2 is unclear. In particular, extrapulmonary manifestationseffects of SARS-CoV-2 infection remain poorly understood. Case series from China and Europe suggest thatthe central nervous system is involved in the disease process in at least a subset of patients, with some reportsestimating up to 30% of COVID-19 patients having neurological symptoms, including seizure, intractableheadache, and impaired smell and taste. Although there are reports of neurological disease in in COVID-19patients, it is unclear if SARS-CoV-2 invades the central nervous system (CNS). Studies of othercoronaviruses, including SARS-CoV-1, demonstrate clear neurotropism as well as neuroinflammationassociated with other members of this family of viruses. These studies raise the possibility that SARS-CoV-2may cause neurological symptoms either through invasion of the CNS or through an increase in inflammatorycytokines within the CNS. We hypothesize that SARS-CoV-2 infections have neuroinvasive potential and leadto altered and hyperinflammatory immune states within the CNS of infected individuals. We further hypothesizethat infection of the CNS exacerbates respiratory dysfunction through direct toxicity of ACE2 expressingneurons that are critical regulators of cardiopulmonary function. Our investigations will combine the power ofhuman studies with those utilizing mouse models in which we can readily administer virus and assess forpathophysiology. Aim 1, we will determine the CNS immune responses in COVID-19 patients withneurological symptoms. Using a combination of single cell RNA-sequencing, cytokine profiling, viralsequencing and antibody validations, we will fully dissect out the inflammatory responses within the CNScompartment compared to the systemic circulation in COVID-19 patients. Using mouse models, in Aim 2, wewill investigate the encephalitic potential of SARS-CoV-2. Using several complementary approaches toinfect mice with SARS-CoV-2, we will introduce the virus into the central nervous system of mice. Usingdepletion antibodies and various knockout mice, we will identify which immune cells are required forneuropathology in these mice through survival studies, flow cytometry and immunofluorescent staining. Finally,in Aim 3, we will evaluate the effects of CNS infection on respiratory outcomes. Because of the knownexpression of ACE2 in the brainstem, and the brainstem's critical role in regulating cardiopulmonary functions,we suspect that CNS infection with SARS-CoV-2 will exacerbate SARS-CoV-2 respiratory disease.These three aims will help support our hypotheses of how SARS-CoV-2 infections can affect the CNS andrespiratory compartments. We expect that our findings will uncover new strategies to treat patients diagnosedwith COVID-19 and help gain new insight to understanding the biology of SARS-CoV-2 pathophysiology.