Sex specific immune response to SARS-CoV-2 leads to chronic neurologic symptoms

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PROJECT SUMMARY To date over 16 million people in the US have been infected with the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). While the vast majority will survive the acute illness, many are at risk for experiencing long-term symptoms after the acute illness. Acute neurologic symptoms including encephalitis, strokes and seizures have been reported in COVID- 19 patients. Increasingly, even survivors without acute neurologic conditions have reported neuropsychiatric symptoms (NPS) months after their illness. The incidence and factors that influence the development of long- term NPS is unknown. SARS-CoV-2 infection triggers a systemic pro-inflammatory response termed `cytokine storm', characterized by an uncontrolled release of pro-inflammatory molecules. The consequences of uncontrolled systemic inflammation on the brain and the link to long-term NPS after COVID-19 is unknown. Sex differences in the outcome from COVID-19 are increasingly evident. Men have worse outcomes with acute COVID-19 infection, with higher hospitalization rates and mortality, an effect seen globally. Sex differences in the immune literature acute inflammatory circulating immune responses underlie the differences i n the acute disease course, as seen both in t he and in our preliminary data. We have found that men have a more robust innate immune response to COVID-19 infection, with increased circulating neutrophils and monocytes and higher serum levels of cytokines and markers of brain injury (neuron specific enolase). In contrast, women have more T and B cells in response to acute infection compared to men, hallmarks of an antigen-specific response.Interestingly, our preliminary data suggest that women however, may be disproportionally affected by the chronic effects of infection, including higher rates of NPS. To examine the mechanism of NPS, we propose a longitudinal, prospective study to assess the impact of acute and chronic inflammation on markers of brain injury, and long-term NPS for up to 2 years after COVID-19 infection. To accomplish this, we will leverage our prospective clinical biorepository and long-term COVID-19 follow-up clinic. To date, over 400 hospitalized COVID-19 patients from three different hospitals have been enrolled into a prospective biorepository and Houston is now at the verge of another surge. Identifying patients at risk for developing chronic consequences of COVID-19 infection, and discovering potential underlying mechanisms leading to NPS will be critical to the enhance the health of millions of COVID-19 survivors.