NK cell mobilization as a pathogenic etiology of SARS-CoV-2 gastrointestinal disease

NK 细胞动员作为 SARS-CoV-2 胃肠道疾病的致病病因

基本信息

批准号：
10626025
负责人：
Roger Keith Reeves
金额：
$ 40.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10626025
关键词：
2019-nCoV Activated Natural Killer Cell Affect Antibodies Antibody Response Antibody-Dependent Enhancement Antigens Antiviral Response Binding COVID-19 COVID-19 patient COVID-19 prevention COVID-19 treatment COVID-19 vaccine Cells Containment Coronavirus Infections Cytomegalovirus Digestive System Disorders Disease Outbreaks Disease Outcome Effector Cell Endowment Epithelium Epitopes Etiology Exhibits Exposure to Future Gastrointestinal Diseases Gastrointestinal tract structure Gut Mucosa HIV Homing Human Immune Immune System Diseases Immune response Immunotherapeutic agent Individual Infection Inflammation Inflammatory Inflammatory Response Influenza Injury Innate Immune System K562 Cells Knowledge Left Macaca Mediating Memory Modeling Mucous Membrane Natural Killer Cells Nucleocapsid Pathogenesis Pathogenicity Pathology Peptides Persons Phenotype Physiologic pulse Play Prevention Primates Property Public Health Reporting Respiratory Disease Respiratory Tract Infections Role SARS-CoV-2 infection SARS-CoV-2 pathogenesis SIV Severity of illness Surface Symptoms T-Lymphocyte Testing Therapeutic Intervention Tissues Vaccines Viral Viral Physiology Virus Virus Diseases Virus Replication Work cytotoxicity data submission experimental study immune function immunopathology influenza infection innovation lung injury mouse model nonhuman primate novel pandemic disease receptor recruit response sensitizing antigen severe COVID-19 trafficking

项目摘要

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of Coronavirus Disease 2019 (COVID-19) and its rapid global spread has led to an unprecedented global public health crisis. Currently, treatment options are very limited and vaccines against SARS-CoV-2 are still pending widespread use. Host immune responses to SARS-CoV-2 play a crucial role in the containment of the infection. Although SARS-CoV-2 is generally thought of as a respiratory disease, an unexpected consequence is severe complications of the gastrointestinal tract (GIT). Indeed, up to two-thirds of COVID-19 patients have some GIT symptoms and several lines of evidence suggest a breakdown of the epithelial barrier resulting in widespread inflammation. While recent studies in COVID-19 patients and nonhuman primate (NHP) models described T lymphocytes and antibody responses, less is known about natural killer (NK) cell responses in SARS-CoV-2 infection. Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections. However, besides their ability to rapidly eliminate virus-infected cells without the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of adaptive capabilities have been identified among human NK cell subpopulations, including reports of true antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. NK cells may be crucial for early containment of SARS-CoV-2 and formation of adaptive responses elicited by infection, yet uncontrolled NK response may also contribute to the hyperinflammatory responses observed in COVID-19 patients, including in the GIT. In this proposal we will use NHP models, which recapitulate viral replication, immune responses and disease pathology observed in human COVID-19 infection, to test the following hypotheses: (i) pathogenic inflammation in the gastrointestinal tract in COVID-19 is a consequence, in part, of dysregulated or exacerbated NK cell responses, and (ii) specific subsets of NK cells mediate potent anti-viral responses against SARS-CoV-2, associated with enhanced viral clearance and reduced disease severity. We will address these hypotheses through two specific aims: 1. Determine the contribution of systemic and GIT NK cell mobilization to SARS-CoV-2 pathogenesis and clearance in macaque models; 2. Evaluate the mechanisms by which specific innate and adaptive NK cell subpopulations modulate SARS-CoV-2 infection in the GIT. If successful, the results of these innovative studies will contribute new knowledge of human immune responses against SARS-CoV-2 and provide the rationale to develop novel immunotherapeutic approaches to target specific NK cell subsets that could substantially contribute to prevent and treat COVID-19.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是冠状病毒的病原体 2019 年疾病 (COVID-19) 及其在全球的快速传播导致了前所未有的全球公共卫生危机。目前，治疗选择非常有限，针对 SARS-CoV-2 的疫苗仍有待广泛应用使用。宿主对 SARS-CoV-2 的免疫反应在遏制感染方面发挥着至关重要的作用。虽然 SARS-CoV-2普遍被认为是一种呼吸道疾病，意想不到的后果是严重的胃肠道（GIT）并发症。事实上，多达三分之二的 COVID-19 患者患有一些胃肠道疾病症状和一些证据表明上皮屏障的破坏导致广泛的炎。虽然最近对 COVID-19 患者和非人灵长类动物 (NHP) 模型的研究描述了 T 淋巴细胞和抗体反应，但人们对 SARS-CoV-2 感染中的自然杀伤 (NK) 细胞反应知之甚少。传统上，NK 细胞被视为先天免疫系统的非特异性效应细胞，发挥着关键作用防御病毒感染。然而，除了它们能够快速消除病毒感染的细胞而无需由于需要事先进行抗原致敏，NK细胞还表现出适应性免疫功能。不同形式的人类 NK 细胞亚群的适应能力已得到证实，包括真实的报告抗原特异性记忆 NK 细胞以及具有增强抗体依赖性功能的适应性 NK 细胞。 NK细胞细胞可能对于早期遏制 SARS-CoV-2 以及由 SARS-CoV-2 引起的适应性反应的形成至关重要感染，但不受控制的 NK 反应也可能导致在 COVID-19 患者，包括胃肠道患者。在本提案中，我们将使用 NHP 模型，该模型概括了病毒在人类 COVID-19 感染中观察到的复制、免疫反应和疾病病理学，以测试以下假设：(i) COVID-19 中胃肠道的致病性炎症是部分原因是 NK 细胞反应失调或加剧，以及 (ii) NK 的特定亚群细胞介导针对 SARS-CoV-2 的有效抗病毒反应，与增强的病毒清除相关并降低疾病的严重程度。我们将通过两个具体目标来解决这些假设： 1. 确定全身和胃肠道 NK 细胞动员对猕猴 SARS-CoV-2 发病机制和清除的贡献模型； 2. 评估特定先天性和适应性 NK 细胞亚群的调节机制胃肠道中的 SARS-CoV-2 感染。如果成功，这些创新研究的结果将贡献新的了解人类针对 SARS-CoV-2 的免疫反应，并为开发新的疫苗提供理论依据针对特定 NK 细胞亚群的免疫治疗方法可大大有助于预防并治疗 COVID-19。