Project 3: Serological Interactions with the Mucosal Innate Immune System Regulates COVID-19 Associated Tissue Damage.

项目 3：血清学相互作用与粘膜先天免疫系统调节 COVID-19 相关组织损伤。

• 批准号: 10222246
• 负责人: Shannon Margaret Wallet
• 金额: $ 72.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222246
• 关键词: 2019-nCoV; Address; Adult Respiratory Distress Syndrome; Affect; Antibodies; Antibody Repertoire; Applied Research; Automobile Driving; B-Lymphocytes; Bacterial Infections; Basic Science; COVID-19; Cell physiology; Cells; Cessation of life; Clinical; Data; Development; Disease; Epithelial Cells; Failure; Hospitalization; Human; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immunologics; Immunosuppression; Individual; Infection; Inflammatory; Inflammatory Response; Inhalation; Injury; Innate Immune Response; Innate Immune System; Interruption; Investigation; Lead; Lung; Lung diseases; Mediating; Middle East Respiratory Syndrome; Molecular; Monoclonal Antibodies; Mucous Membrane; Natural Immunity; Nature; North Carolina; Outcome; Pathogenesis; Pathogenicity; Patients; Peripheral; Phase; Regulation; Research; Resolution; Respiratory distress; Serologic tests; Serological; Severe Acute Respiratory Syndrome; Severities; Shapes; Site; Surface; Symptoms; T-Lymphocyte; Testing; Therapeutic; Tissues; Viral; clinical biomarkers; experience; immune function; improved; indexing; innate immune function; innate immune mechanisms; macrophage; mouse model; neutrophil; novel; pathogen; polyclonal antibody; respiratory; response

Abstract. The UNC Center for Excellence in SARS-CoV2 Serologic Research uses basic and applied research strategies to improve our understanding of the molecular and cellular mechanisms driving serological and humoral immune responses after SARS-CoV2 infection. COVD-19 pathogenesis can take a mild course with few or no symptoms or it can progress to a more severe state requiring hospitalization and often results in respiratory distress, secondary bacterial infections and death. It is clear the severity is due to the type and magnitude of the immunological response to SARS-CoV2 infection. There is very little information about the independent and cooperative effects of all phases of the immune response: innate and adaptive, namely humoral (B cell/serologic), and cellular (T cell) and their clinical sequelae in COVID-19. However, clinical outcomes (pulmonary hyper-inflammatory responses with concurrent immune suppression) of COVID-19 are strikingly similar to that which we have studied with lung inhalation injuries and unresolved oronasalpharyngeal inflammatory responses. Indeed, we and others have defined that the nature and magnitude of an innate immune response to a pathogen directly affects the nature and magnitude of the specific humoral response systemically and in the pathogen-tropic tissue (i.e. oronasopharynx/lung). Resulting antibodies (Ab) also shape many subsequent innate immune functions of canonical immune cells such as neutrophils and macrophages, as well as barrier functions of mucosal cells such as epithelial cells. The additive effect of these interactions directly impacts the short- and long-lived Ab repertoire. Taken together, this Project will focus our investigations on defining unique and overlapping mechanisms of the mucosal immune-mediated pathogenesis of COVID-19 which lead to mild and severe disease. We hypothesize that the bi-directional interactions between the innate immune response and the serologic immune response regulate and shape the severity of COVID-19. We will test this hypothesis by 1) revealing pulmonary and systemic innate immune signatures, as a function of serology across the span of natural disease in human patients, to identify indices which promote development of protective versus pathogenic Ab repertoires, while 2) delineating mechanisms of polyclonal and monoclonal Ab mediated activation and suppression of innate immune and mucosal cell function which drive severe versus mild disease in murine models of COVID-19. Taken together, these data will inform us both mechanistically and therapeutically, defining antibody repertoires that can interrupt or ameliorate disease. The integrated expertise of our Team and the Center as a whole is necessary and sufficient to address the novel cross-cutting hypotheses put forth which will improve our understanding of SARS-CoV2 serological and humoral immunity.

抽象的。 北卡罗来纳大学 SARS-CoV2 血清学研究卓越中心利用基础和应用研究 提高我们对驱动血清学和细胞学机制的理解的策略 SARS-CoV2 感染后的体液免疫反应。 COVD-19 的发病机制可能是温和的 很少或没有症状，或者可能发展到需要住院治疗的更严重的状态，并且通常会导致 呼吸窘迫、继发细菌感染和死亡。很明显，严重程度取决于类型和 对 SARS-CoV2 感染的免疫反应的强度。关于该的信息非常少 免疫反应所有阶段的独立和协同效应：先天性和适应性，即体液 （B 细胞/血清学）和细胞（T 细胞）及其在 COVID-19 中的临床后遗症。然而，临床结果 COVID-19 的（肺部高炎症反应并伴有免疫抑制）令人震惊 类似于我们对肺部吸入性损伤和未解决的口鼻咽部损伤的研究 炎症反应。事实上，我们和其他人已经定义了先天免疫的性质和程度 对病原体的反应直接影响全身特定体液反应的性质和程度 以及嗜病原体组织（即口鼻咽/肺）。由此产生的抗体 (Ab) 也塑造了许多 典型免疫细胞（例如中性粒细胞和巨噬细胞）随后的先天免疫功能，以及 作为粘膜细胞如上皮细胞的屏障功能。这些相互作用的直接累加效应 影响短期和长期的抗体库。 总的来说，这个项目将把我们的研究重点放在定义独特和重叠的机制上。 COVID-19 的粘膜免疫介导的发病机制可导致轻度和重度疾病。我们假设 先天免疫反应和血清免疫之间的双向相互作用 应对措施调节并影响 COVID-19 的严重程度。我们将通过以下方式检验这一假设：1）揭示肺部 和系统性先天免疫特征，作为人类自然疾病范围内血清学的函数 患者，以确定促进保护性抗体库和致病性抗体库发展的指标，同时 2) 描述多克隆和单克隆抗体介导的先天免疫激活和抑制的机制 在 COVID-19 小鼠模型中，驱动严重与轻度疾病的粘膜细胞功能。采取 总之，这些数据将从机制和治疗上为我们提供信息，定义抗体库 可以中断或改善疾病。我们团队和整个中心的综合专业知识是必要的 并足以解决提出的新颖的跨领域假设，这将提高我们对 SARS-CoV2 血清学和体液免疫。