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

抽象的。 北卡罗来纳大学SARS-CoV2血清学研究卓越中心使用基础和应用研究 策略，以提高我们对分子和细胞机制的理解，推动血清学和 SARS-CoV2感染后的体液免疫反应。COVD-19的发病机制可以采取温和的过程 很少或没有症状，或者可以发展到需要住院治疗的更严重的状态，通常导致 呼吸窘迫、继发性细菌感染和死亡。很明显，严重程度是由于类型和 对SARS-CoV2感染的免疫反应的大小。关于这一事件的信息很少 免疫反应各阶段的独立和协同效应：先天和适应性，即体液 (B细胞/血清学)、细胞(T细胞)及其在新冠肺炎中的临床后遗症。然而，临床结果 新冠肺炎(肺高炎性反应伴免疫抑制)令人震惊 类似于我们对肺吸入性损伤和未解决的口鼻咽部的研究 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大小 对病原体的反应直接影响系统特异性体液反应的性质和大小 在致病组织中(即口鼻咽/肺)。由此产生的抗体(Ab)也塑造了许多 中性粒细胞和巨噬细胞等规范免疫细胞随后的先天免疫功能 作为黏膜细胞的屏障功能，如上皮细胞。这些相互作用的直接相加效应 影响短命和长寿的抗体曲目。 综上所述，本项目将把我们的调查重点放在定义 黏膜免疫介导的新冠肺炎轻、重病发病机制。我们假设 先天免疫反应和血清免疫之间的双向相互作用 应对措施规范和塑造了新冠肺炎的严重性。我们将通过1)揭示肺脏来验证这一假设 和系统性先天免疫特征，作为人类自然疾病跨度的血清学功能 患者，以确定促进保护性抗体相对于致病性抗体谱系发展的指标，而2) 多克隆和单抗介导的天然免疫激活和抑制机制的研究 以及粘膜细胞功能在新冠肺炎小鼠模型中驱动重度疾病与轻度疾病的作用。已被占用 总而言之，这些数据将从机制和治疗上告诉我们，定义抗体谱系 可以中断或改善疾病。我们团队和中心作为一个整体的综合专业知识是必要的 并足以解决提出的新的横切假设，这将提高我们对 SARS-CoV2血清学和体液免疫。

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.