Regulation of lung inflammatory and antiviral responses during coronavirus infection

父R01摘要 先天免疫系统是抵御病原体感染的关键第一道防线。在…的背景下 病毒感染，激活先天免疫反应是控制病毒复制和消除 感染。然而，这种反应的过度激活可能会导致全身性炎症和显著 发病率和死亡率。最近，一种新的冠状病毒SARS-CoV-2出现，导致了这种疾病 新冠肺炎和一场全球大流行。严重缺乏有针对性的治疗策略，而且有限 了解先天免疫反应在本病中的作用。临床数据显示，患有 新冠肺炎经历了一场细胞因子风暴和严重的组织损伤，这两者都是导致疾病的因素 严重程度和死亡率。我们小组最近的研究表明，在以下情况下，肿瘤坏死因子-α和干扰素-γ水平增加 SARS-CoV-2感染会导致炎性细胞死亡，对宿主不利。我们发现 中和肿瘤坏死因子-α和干扰素-γ可降低SARS-CoV-2诱导的小鼠死亡率。但人们对此知之甚少 细胞因子释放失控背后的机制基础。虽然几种潜在的治疗方法可以阻止不同的 正在探索炎性细胞因子，平衡促炎症反应以清除病毒 预防全身性炎症仍然具有挑战性。提高了对以下机制的理解 先天免疫系统识别和应对冠状病毒感染将是告知和 制定治疗策略。此外，特定的先天免疫感受器、炎症体的作用 新冠肺炎疾病发生发展过程中的激活、炎性细胞死亡等机制尚不清楚。我们有 先前阐明了调节炎症的先天免疫信号通路的分子细节 以及致病清除，识别上游传感器和这些途径中的重要分子。在这 应用，我们试图揭开新的先天免疫传感器和 之前在我们实验室发现的炎症体调节因子，并理解它们与细胞死亡的串扰 冠状病毒感染的监管机构。支持这一研究领域的基础科学对理解 先天免疫反应的基本原理。根据这项提议完成的工作将具有以下特点 直接感应SARS-CoV-2以启动干扰素和炎症的主要先天免疫传感器 细胞因子的表达及其调控炎症细胞死亡的分子机制 SARS-CoV-2。这些发现有望确定可能成为靶点的新的信号通路 通过治疗干预。这一发现不仅适用于新冠肺炎，也适用于其他传染性疾病 与过度活跃的先天免疫反应、细胞因子释放和严重的 炎症；这项工作将是提供预防发病率和死亡率的临床指导的基础。

PARENT R01 ABSTRACT The innate immune system is the critical first line of defense against pathogenic infections. In the context of viral infections, activation of the innate immune response is key to controlling viral replication and eliminating the infection. However, overactivation of this response can lead to systemic hyperinflammation and significant morbidity and mortality. Recently, a novel coronavirus, SARS-CoV-2, has emerged, leading to the disease COVID-19 and a global pandemic. Targeted therapeutic strategies are critically lacking, and there is limited understanding of the role of innate immune responses in this disease. Clinical data show that patients with COVID-19 experience a cytokine storm and significant tissue damage, both of which contribute to disease severity and mortality. Recent work from our group showed that increased TNF-α and IFN-γ levels following SARS-CoV-2 infection lead to inflammatory cell death, which is detrimental to the host. We found that neutralizing TNF-α and IFN-γ reduced SARS-CoV-2–induced mortality in mice. But little is known about the mechanistic basis behind the uncontrolled cytokine release. While several potential therapies to block different inflammatory cytokines are being explored, balancing proinflammatory responses to clear the virus with preventing systemic inflammation remains challenging. Improved understanding of the mechanisms by which the innate immune system recognizes and responds to coronavirus infections will be key to informing and developing therapeutic strategies. Furthermore, the roles of specific innate immune sensors, inflammasome activation, and inflammatory cell death in COVID-19 disease development remain unknown. We have previously elucidated the molecular details of innate immune signaling pathways that regulate inflammation and pathogenic clearance, identifying upstream sensors and important molecules in these pathways. In this grant application, we seek to unravel the fundamental mechanisms of novel innate immune sensors and inflammasome regulators discovered in our lab previously and understand their crosstalk with cell death regulators in coronavirus infection. Basic science supporting this area of research is critical to understanding the fundamentals of the innate immune response. The work completed under this proposal will characterize the major innate immune sensors that are directly sensing SARS-CoV-2 to initiate interferon and inflammatory cytokine expression and identify the molecular mechanisms that regulate inflammatory cell death in response to SARS-CoV-2. These discoveries are expected to identify novel signaling pathways that could be targeted by therapeutic interventions. The findings will be applicable to not only COVID-19, but also other infectious diseases and conditions associated with a hyperactive innate immune response, cytokine release, and severe inflammation; this work will be fundamental to inform clinical directions to prevent morbidity and mortality.