Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects

项目摘要 由SARS-CoV-2病毒引起的2019冠状病毒病（COVID-19）已经导致近3 全世界有100万例实验室诊断感染和20多万例死亡。没有已知的预先存在的 对人类SARS-CoV-2的免疫力或获得许可的治疗方法来对抗或限制感染。在没有 这些药物干预，世界各国政府已实施严格的措施， 这些措施遏制了SARS-CoV-2向有感染严重并发症风险的人群的传播。努力 确定有效疗法和开发疫苗以对抗感染和疾病需要时间， 需要对这种新型病原体有深入的了解特别是免疫导向疗法 需要详细了解不仅在严重的COVID-19疾病中产生的免疫反应， 在绝大多数发展为非严重疾病的个体中也是如此。先天免疫系统是 反应，以对付感染的早期阶段，但也是至关重要的调节随后的适应性 免疫反应在人类中，抗SARS-CoV-2的体液免疫获得了显著的关注， 对于先天免疫和记忆T细胞反应尚未进行广泛研究。然而，知识 从SARS-CoV-1研究中获得的结果表明，T细胞免疫在病毒控制中至关重要。在这些SARS-CoV-1 在感染的小鼠中，先天性I型干扰素信号级联的诱导被延迟。然而缺乏这种能力的老鼠 先天性免疫应答在他们的肺中表现出更多数量的病毒特异性T细胞。因此， 先天免疫应答失调损害抗SARS-CoV-1T细胞记忆。是否SARS-CoV-2 感染诱导保护性记忆T细胞，如果抗SARS-CoV-2 T细胞记忆的持久性 受先天免疫影响的基因目前都还未被研究。在人类中，先天性免疫反应诱导在 非严重COVID-19疾病的特征尚不明确。然而，对培养细胞和 动物模型表明，在SARS-CoV-2感染后， 免疫力导致对免疫细胞募集至关重要的细胞因子和趋化因子的有限诱导。我们 预测绝大多数COVID-19感染者将表现出先天免疫失调， 反应典型的延迟和有限的炎症信号。如果这是真的，这种受损的先天免疫系统 免疫应答反过来又会诱导有限的短期适应性免疫。事实上，SARS-CoV-1的研究 感染表明体液应答在恢复的患者中是短暂的。据我们所知，没有研究 研究了COVID-19受试者的记忆持久性。在本提案中，我们将询问来自 前瞻性纵向队列的西雅图居民，以检查是否异常T细胞记忆诱导期间， SARS-CoV-2感染，重要的是，这种受损的记忆是否源于先天免疫失调。 此外，在hACE2转基因小鼠模型中的机制研究，其中SARS-CoV-2感染导致 在轻度疾病中，将确定先天免疫如何形成抗SARS CoV-2 T细胞反应。

PROJECT SUMMARY Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has already resulted in nearly 3 million laboratory diagnosed infections and over 200,000 deaths worldwide. There is no known pre-existing immunity to SARS-CoV-2 in humans or licensed therapeutics to combat or limit infection. In the absence of these pharmacological interventions, governments around the world have implemented stringent measures to that curb the spread of SARS-CoV-2 to populations at risk of serious complications from infection. Efforts to identify efficacious therapies and develop vaccines to counter infection and disease require time and ultimately need to be guided by deep knowledge about this novel pathogen. Immune-directed therapies in particular require a detailed understanding of the immune responses generated not only in severe COVID-19 disease but also in the vast majority of individuals who develop non-severe disease. Innate immunity serves as the frontline response to counter the early stages of infection and but is also critical for regulating the ensuing adaptive immune response. In humans, anti-SARS-CoV-2 humoral immunity has gained significant attention while roles for innate immunity and memory T cell responses have not been extensively studied. However, knowledge gained from SARS-CoV-1 studies indicate that T cell immunity is critical in virus control. In these SARS-CoV-1 infected mice, the induction of the innate type I Interferon signaling cascade is delayed. Yet mice lacking this innate immune response exhibited greater numbers of virus specific T cells in their lungs. Thus, this dysregulated innate immune response impairs anti-SARS-CoV-1 T cell memory. Whether SARS-CoV-2 infection induces protective memory T cells and if the durability of anti-SARS-CoV-2 T cell memory is influenced by innate immunity are all currently unexplored. In humans, the innate immune response induced in non-severe COVID-19 disease is not well characterized. However, preliminary studies in cultured cells and animal models indicate that upon SARS-CoV-2 infection, there is a restricted and delayed induction of innate immunity resulting in limited induction of cytokines and chemokines critical for immune cell recruitment. We predict that the vast majority of COVID-19 infected individuals will exhibit a dysregulated innate immune response typified by delayed and limited inflammatory signaling. If true, such a compromised innate immune response could in turn induce limited short-lived adaptive immunity. Indeed, studies from SARS-CoV-1 infections indicate that humoral responses are short-lived in recovered patients. To our knowledge, no studies have examined memory durability in COVID-19 subjects. In this proposal, we will interrogate samples from a prospective longitudinal cohort of Seattle residents to examine if aberrant T cell memory is induced during SARS-CoV-2 infection and importantly if this impaired memory stems from dysregulated innate immunity. Furthermore, mechanistic studies in the hACE2 transgenic mouse model, where SARS-CoV-2 infection results in mild disease, will identify how innate immunity shapes anti-SARS CoV-2 T cell responses.