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

评估 SARS-CoV-2 感染人类受试者持久保护性免疫力的决定因素

基本信息

批准号：
10375774
负责人：
Stefan HI Kappe
金额：
$ 36.73万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-16 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375774
关键词：
2019-nCoV Activities of Daily Living Address Animal Model Antibodies Antibody titer measurement Antigens Attention Avidity B-Cell Antigen Receptor B-Lymphocyte Subsets B-Lymphocytes Biological Assay Blood Circulation Body Regions COVID-19 Cell Culture Techniques Cell model Cells Cessation of life Characteristics China Clinical Trials Critical Illness Cultured Cells Data Development Disease Epithelial Cells Exhibits Fc Receptor Future Goals Government Human Humoral Immunities Immune Immune response Immune system Immunity Immunization Immunologic Memory Immunotherapy Impairment In Vitro Individual Infection Inflammatory Innate Immune Response Interferon Type I Intervention Knowledge Laboratory Diagnosis Longevity Longitudinal cohort Lung Macaca mulatta Malaria Measures Medical Memory Memory B-Lymphocyte Memory impairment Methodology Monoclonal Antibodies Mus Natural Immunity New York City Outcome Outcome Study Parents Patients Pharmacology Polysaccharides Populations at Risk Production Reagent Recombinant Antibody Recovery Research Role SARS coronavirus SARS-CoV-2 antibody SARS-CoV-2 immunity SARS-CoV-2 infection Sampling Serum Shapes Signal Transduction Social Distance Social Policies Sorting - Cell Movement Symptoms T cell response T memory cell T-Lymphocyte Technical Expertise Techniques Testing Therapeutic Therapeutic Monoclonal Antibodies Time Transgenic Mice Vaccine Design Viral Virus Virus Diseases Virus Replication Work Zoonoses adaptive immune response adaptive immunity chemokine cohort combat cytokine efficacious treatment emerging pathogen experience mouse model neutralizing antibody novel novel therapeutics pandemic disease prevent prospective receptor binding recruit response serosurvey severe COVID-19 single cell sequencing social influence stem tool vaccine development

项目摘要

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.

项目总结由SARS-CoV-2病毒引发的2019年冠状病毒病(新冠肺炎)已造成近3 全球有100万人被实验室诊断为感染，20多万人死亡。没有已知的预先存在的人类对SARS-CoV-2的免疫力或获得许可的治疗方法以对抗或限制感染。在没有的情况下在这些药物干预下，世界各国政府都采取了严格的措施来这抑制了SARS-CoV-2病毒向感染严重并发症风险人群的传播。努力实现确定有效的治疗方法和开发疫苗来对抗感染和疾病需要时间和最终需要以对这种新病原体的深入了解为指导。特别是免疫导向疗法需要详细了解不仅在严重的新冠肺炎病中产生的免疫反应，而且在发展为非严重疾病的绝大多数人中也是如此。先天免疫作为前线反应以对抗感染的早期阶段，但也是调节随后的适应性的关键免疫反应。在人类中，抗SARS-CoV-2体液免疫在发挥作用的同时，也受到了极大的关注对于先天免疫和记忆，T细胞反应还没有得到广泛的研究。然而，知识 SARS-CoV-1研究表明，T细胞免疫在病毒控制中至关重要。在这些SARS-CoV-1中感染小鼠后，先天I型干扰素信号级联的诱导被延迟。然而，缺乏这一点的老鼠先天免疫反应在他们的肺中表现出更多的病毒特异性T细胞。因此，这一点调节失调的先天免疫反应损害抗SARS-CoV-1 T细胞记忆。SARS-CoV-2是否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的影响，目前都是未知的。在人类中，诱导的先天免疫反应非重症新冠肺炎病的特点不好。然而，在培养细胞和动物模型表明，在SARS-CoV-2感染后，先天的诱导受到限制和延迟。免疫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。我们预测绝大多数新冠肺炎感染者将表现出调节失调的先天免疫以延迟和有限的炎症信号为典型的反应。如果是真的，这种受损的先天免疫力反应反过来又能诱导有限的短暂适应性免疫。事实上，对SARS-CoV-1的研究感染表明，康复患者的体液反应是短暂的。据我们所知，没有研究研究了新冠肺炎受试者的记忆耐久性。在这份提案中，我们将询问来自对西雅图居民进行前瞻性纵向队列研究，以检查在 SARS-CoV-2感染，更重要的是，如果这种记忆受损源于调节失调的先天免疫。此外，在hACE2转基因小鼠模型中，SARS-CoV-2感染导致的机制研究在轻度疾病中，将确定先天免疫如何塑造抗SARS CoV-2 T细胞反应。