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：
10265628
负责人：
Stefan HI Kappe
金额：
$ 71.28万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-06 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265628
关键词：
Address Africa Antibodies Area Attenuated B-Lymphocytes Blood Blood Circulation Capsid Proteins Cells Chemicals Clinical Clinical Trials Communicable Diseases Country Cues Data Development Disease Effector Cell Future Generations Goals Human Immune Immune response Immune system Immunity Immunization Immunologic Memory Immunology Individual Infection Inflammatory Response Innate Immune Response Innate Immune System Lead Lymphocyte Maintenance Malaria Malaria Vaccines Measures Mediating Memory Modeling Mus Organ Outcome Parasites Parasitology Plasmodium Plasmodium falciparum Population Prevention Process Research Residencies Sampling Sentinel Sporozoite vaccine Sporozoites Sterility Subunit Vaccines Surface System T-Lymphocyte Techniques Testing Time Tissues Vaccination Vaccine Design Vaccines adaptive immune response base circumsporozoite protein clinically relevant experience insight malaria infection mouse model novel programs research clinical testing response tool vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine trial vaccinology

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.

项目概要由 SARS-CoV-2 病毒引起的 2019 年冠状病毒病 (COVID-19) 已导致近 3 例全球有 100 万人被实验室确诊感染，死亡人数超过 20 万人。没有已知的预先存在的人类对 SARS-CoV-2 的免疫力或用于对抗或限制感染的许可疗法。在没有这些药物干预措施，世界各国政府都采取了严格的措施遏制 SARS-CoV-2 向有感染严重并发症风险的人群传播。努力确定有效的疗法并开发疫苗来对抗感染和疾病需要时间，最终需要以对这种新型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 COVID-19 疾病中产生的免疫反应，而且绝大多数患有非严重疾病的人也有这种情况。先天免疫是前线应对感染早期阶段的反应，但对于调节随后的适应性也至关重要免疫反应。在人类中，抗 SARS-CoV-2 体液免疫已引起广泛关注，同时发挥作用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 SARS-CoV-1 研究表明，T 细胞免疫对于病毒控制至关重要。在这些 SARS-CoV-1 受感染的小鼠，先天 I 型干扰素信号级联的诱导被延迟。然而老鼠却缺乏这一点先天免疫反应在肺部显示出更多数量的病毒特异性 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。是否为 SARS-CoV-2 感染会诱导保护性记忆 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因素目前尚未被探索。在人类中，先天免疫反应在非重症 COVID-19 疾病的特征尚不明确。然而，在培养细胞中的初步研究动物模型表明，SARS-CoV-2 感染后，先天性诱导受到限制且延迟。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诱导有限。我们预测绝大多数 COVID-19 感染者将表现出先天免疫失调以延迟和有限的炎症信号传导为代表的反应。如果属实，那么先天免疫系统就会受到损害反应反过来可能会诱导有限的短期适应性免疫。事实上，针对 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，没有研究研究人员检查了 COVID-19 受试者的记忆持久性。在本提案中，我们将询问来自对西雅图居民进行前瞻性纵向队列研究，以检查异常 T 细胞记忆是否在 SARS-CoV-2 感染，更重要的是，这种记忆受损是否源于先天免疫失调。此外，在 hACE2 转基因小鼠模型中进行了机制研究，其中 SARS-CoV-2 感染导致在轻度疾病中，将确定先天免疫如何影响抗 SARS CoV-2 T 细胞反应。