权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting innate immune pathways, and inflammatory cell death in cytokine-mediated diseases

针对细胞因子介导疾病中的先天免疫途径和炎症细胞死亡

基本信息

批准号：
10311802
负责人：
Thirumala-Devi Kanneganti
金额：
$ 76.38万
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/10311802
关键词：
2019-nCoV 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 Influenza A virus Innate Immune Response Innate Immune System Interferon Type II Interferons Interleukin-1 beta Interleukin-18 Lead Mediating Molecular Morbidity - disease rate Mus Natural Immunity Paper Pathogenicity Pathology Pathway interactions Peer Review Play Procedures Production Publications Publishing RIPK1 gene RIPK3 gene RNA Viruses Receptor Signaling 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 innate immune pathways innovation insight interest microbial mortality novel novel coronavirus novel therapeutic intervention pandemic disease pathogen prevent respiratory response sensor systemic inflammatory response targeted treatment

项目摘要

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.

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。