Regulation of lung inflammatory and antiviral responses during coronavirus infection

冠状病毒感染期间肺部炎症和抗病毒反应的调节

基本信息

批准号：
10631757
负责人：
Thirumala-Devi Kanneganti
金额：
$ 39.34万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631757
关键词：
2019-nCoV Antiviral Response Applications Grants Area Basic Science Biological CASP3 gene CASP6 gene CASP8 gene COVID-19 COVID-19 mortality COVID-19 pandemic COVID-19 patient COVID-19 treatment Cell Death Cell Line Cells Clinical Clinical Data Communicable Diseases Complex Coronavirus Coronavirus Infections Data Analyses Development Disease Ensure Equilibrium Functional disorder Future Grant Human Hyperactivity Immune Immune signaling Immunology Infection Inflammasome Inflammation Inflammatory Inflammatory Response Influenza A virus Innate Immune Response Innate Immune System Interferon Type II Interferons Interleukin-1 beta Interleukin-18 Lead Lung Mediating Molecular Morbidity - disease rate Mus Natural Immunity Paper Parents Pathogenicity Pathology Pathway interactions Peer Review Play Procedures Production Publications Publishing RIPK1 gene RIPK3 gene RNA Viruses Receptor Signaling Regulation Reproducibility Research Role Severity of illness Signal Pathway TNF gene Therapeutic Therapeutic Intervention Tissues Toll-like receptors Viral Viral Pathogenesis Virus Virus Diseases Virus Replication Work base coronavirus disease cytokine cytokine release syndrome experience global health human disease improved in vivo innate immune mechanisms innovation insight interest microbial mortality novel novel coronavirus novel therapeutic intervention pandemic disease pathogen prevent respiratory response sensor systemic inflammatory response targeted treatment translational potential

项目摘要

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.

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。病毒感染时，先天免疫反应的激活是控制病毒复制和消除病毒的关键然而，这种反应的过度激活可能导致全身过度炎症和严重的感染。最近，一种新型冠状病毒 SARS-CoV-2 的出现，导致了这种疾病。 COVID-19 和全球大流行严重缺乏针对性的治疗策略，而且数量有限。了解先天免疫反应在这种疾病中的作用的临床数据表明，患者。 COVID-19 经历细胞因子风暴和严重的组织损伤，这两者都会导致疾病我们小组最近的研究表明，TNF-α 和 IFN-γ 水平随着时间的推移而增加。我们发现，SARS-CoV-2 感染会导致炎症细胞死亡，这给宿主带来痛苦。中和 TNF-α 和 IFN-γ 可降低 SARS-CoV-2 诱导的小鼠死亡率，但对此我们知之甚少。不受控制的细胞因子释放背后的机制基础，同时有几种潜在的疗法可以阻止不同的情况。正在探索炎症细胞因子，平衡促炎反应以清除病毒预防全身性炎症仍然具有挑战性。先天免疫系统识别并应对冠状病毒感染将是通报和应对冠状病毒感染的关键此外，特定先天免疫传感器、炎症小体的作用。我们尚不清楚 COVID-19 疾病发展中的激活和炎症细胞死亡。先前阐明了调节炎症的先天免疫信号通路的分子细节和病原体清除，识别这些途径中的上游传感器和重要分子。拨款申请中，我们寻求揭示新型先天免疫传感器的基本机制和我们实验室之前发现了炎症小体调节因子，并了解它们与细胞死亡的串扰支持这一研究领域的基础科学对于理解冠状病毒感染至关重要。根据本提案完成的工作将描述先天免疫反应的基本原理。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表达并确定调节炎症细胞死亡反应的分子机制这些发现有望确定可针对的新信号通路。研究结果不仅适用于 COVID-19，还适用于其他传染病。与先天免疫反应过度活跃、细胞因子释放和严重相关的疾病和病症炎症；这项工作对于指导预防发病和死亡的临床方向至关重要。