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

• 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
• 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

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.

项目摘要 由SARS-COV-2病毒引起的2019年冠状病毒病（COVID-19）已经导致了近3个 百万实验室诊断出感染和全球超过200,000人死亡。没有已知的先前存在的 对人类或有执照的治疗剂的SARS-COV-2免疫，以对抗或限制感染。在没有 这些药理干预措施，世界各地的政府已采取了严格的措施 这遏制了SARS-COV-2对感染严重并发症风险的种群的传播。努力 确定有效的疗法并开发疫苗以抵消感染和疾病需要时间，最终需要时间 需要以对这种新型病原体的深入了解来指导。免疫定向疗法 需要详细了解不仅在严重的Covid-19疾病中产生的免疫反应，还需要 同样在大多数发展非严重疾病的人中。先天免疫作为前线 反应应对感染的早期阶段，但对于调节随后的适应性也很重要 免疫反应。在人类中，抗SARS-COV-2体液免疫已引起了很大的关注，而角色 对于先天的免疫力和记忆力，尚未广泛研究T细胞反应。但是，知识 从SARS-COV-1研究中获得的表明，T细胞免疫在病毒控制中至关重要。在这些SARS-COV-1中 被感染的小鼠，ISHATE I型干扰素信号级联反应的诱导延迟。但是老鼠缺乏这个 先天免疫反应在其肺中表现出更多的病毒特异性T细胞。因此，这个 失调的先天免疫反应会损害抗SARS-COV-1 T细胞记忆。是否SARS-COV-2 感染会诱导保护性记忆T细胞，以及抗Sars-Cov-2 T细胞存储器的耐用性 受先天免疫的影响目前尚未探索。在人类中，诱发的先天免疫反应 非严重的covid-19疾病没有很好地表征。但是，在培养细胞和 动物模型表明，在SARS-COV-2感染后，有限制和延迟的先天诱导 免疫力导致细胞因子的诱导有限，而趋化因子对免疫细胞募集至关重要。我们 预测绝大多数Covid-19受感染的个体将表现出失调的先天免疫 反应以延迟和有限的炎症信号传导为代表。如果是真的，那么这种损害的先天免疫 反应反过来可能诱导有限的短期适应性免疫。确实，SARS-COV-1的研究 感染表明，在恢复的患者中，体液反应是短暂的。据我们所知，没有研究 已经检查了COVID-19受试者中的记忆耐用性。在此建议中，我们将从 西雅图居民的前瞻性纵向队列检查是否诱发了异常的T细胞记忆 SARS-COV-2感染，重要的是，如果这种记忆力受损源自先天免疫失调。 此外，HACE2转基因小鼠模型中的机理研究，其中SARS-COV-2感染结果 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。