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

项目摘要 迄今为止，美国已有超过1600万人感染严重急性呼吸道综合征 冠状病毒2型病毒（SARS-CoV-2），导致2019冠状病毒病（COVID-19）。虽然绝 大多数人会在急性疾病中幸存下来，许多人在急性疾病后有经历长期症状的风险。 病急性神经系统症状包括脑炎，中风和癫痫发作已报告在COVID- 19名患者。越来越多的情况是，即使没有急性神经系统疾病的幸存者也报告有神经精神疾病 病后几个月的症状。影响长- 术语“未知”。SARS-CoV-2感染引发称为“细胞因子”的全身促炎反应 风暴”，其特征在于促炎分子的不受控制的释放。的后果 大脑不受控制的全身性炎症以及与COVID-19后长期患病的联系尚不清楚。 COVID-19结果的性别差异越来越明显。男性的结果更糟， 急性COVID-19感染，住院率和死亡率更高，这是全球范围内的影响。性 免疫差异 文学 急性 炎性 循环 免疫 反应是急性病程差异的基础，正如在两种疾病中所看到的， 在我们的初步数据中。我们发现，男性有一个更强大的先天免疫反应， COVID-19感染，循环中性粒细胞和单核细胞增加， 细胞因子和脑损伤标志物（神经元特异性烯醇化酶）。相比之下，女性拥有更多 与男性相比，T和B细胞对急性感染的反应， 有趣的是，我们的初步数据表明，妇女，然而，可能是谨慎的， 受感染的慢性影响，包括更高的感染率。为了研究脑梗死的机制， 我们提出了一项纵向的前瞻性研究，以评估急性和慢性炎症对 脑损伤的标志物，以及COVID-19感染后长达2年的长期隔离。为了做到这一点，我们 将利用我们的前瞻性临床生物储存库和长期COVID-19随访诊所。迄今为止， 来自三家不同医院的住院COVID-19患者已被纳入前瞻性研究， 休斯顿现在正处于另一个激增的边缘。识别有发展风险的患者 COVID-19感染的慢性后果，并发现导致 这将对改善数百万COVID-19幸存者的健康至关重要。

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.