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

• 批准号: 10319735
• 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
• 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/10319735
• 关键词: 2019-nCoV; Activated Natural Killer Cell; Address; Affect; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antigens; Antiviral Agents; Antiviral Response; Binding; COVID-19; COVID-19 patient; COVID-19 prevention; COVID-19 treatment; COVID-19 vaccine; Cells; Containment; Coronavirus Infections; Cytomegalovirus; Data; Digestive System Disorders; Disease Outbreaks; Disease Outcome; Effector Cell; Epithelial; 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; Influenza; Injury; Innate Immune System; K562 Cells; Knowledge; Left; Lung diseases; 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 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; base; cytotoxicity; 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

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型（SARS-CoV-2）是冠状病毒的病原体 2019年新型冠状病毒病（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的疫苗仍有待推广 使用.宿主对SARS-CoV-2的免疫反应在遏制感染方面起着至关重要的作用。虽然 SARS-CoV-2通常被认为是一种呼吸道疾病，意外后果严重 胃肠道并发症（GIT）。事实上，多达三分之二的COVID-19患者患有GIT 症状和一些证据表明上皮屏障的破坏导致广泛的 炎症 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，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细胞被认为是先天免疫系统的非特异性效应细胞， 来抵御病毒感染然而，除了它们能够迅速消除病毒感染的细胞， 由于需要预先抗原致敏，NK细胞也表现出适应性免疫功能。不同形式的 在人类NK细胞亚群中已经确定了适应能力，包括真实的 抗原特异性记忆NK细胞以及具有增强的抗体依赖性功能的适应性NK细胞。NK 细胞可能是早期遏制SARS-CoV-2和形成适应性反应的关键， 感染，但不受控制的NK反应也可能有助于观察到的高炎症反应， COVID-19患者，包括GIT患者。在这个建议中，我们将使用NHP模型，它概括了病毒 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一种 结果，部分失调或恶化的NK细胞反应，和（ii）NK细胞的特定子集， 细胞介导针对SARS-CoV-2的有效抗病毒应答，与增强的病毒清除相关 并降低疾病严重程度。我们将通过两个具体目标来解决这些假设：1。确定 猕猴全身和GIT NK细胞动员对SARS-CoV-2发病和清除的贡献 模型; 2.评估特异性先天性和适应性NK细胞亚群调节的机制 GIT中的SARS-CoV-2感染。如果成功的话，这些创新研究的结果将有助于新的 了解人类对SARS-CoV-2的免疫应答，并为开发新的 靶向特定NK细胞亚群的免疫方法， 治疗新冠肺炎