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

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.
PAGERR 01摘要 先天免疫系统是抵抗病原性感染的关键第一道防线。背景下 在病毒感染时,先天免疫反应的激活是控制病毒复制和消除病毒感染的关键。 感染然而,这种反应的过度激活可导致全身性炎症过度和显著的炎症反应。 发病率和死亡率。最近,一种新型冠状病毒SARS-CoV-2出现,导致了这种疾病 COVID-19和全球大流行。目前严重缺乏有针对性的治疗策略, 了解先天免疫反应在这种疾病中的作用。临床数据显示, COVID-19经历了细胞因子风暴和显著的组织损伤,这两者都有助于疾病 严重程度和死亡率。我们小组最近的工作表明,在以下情况下,TNF-α和IFN-γ水平增加 SARS-CoV-2感染导致炎性细胞死亡,这对宿主是不利的。我们发现 中和TNF-α和IFN-γ可降低SARS-CoV-2诱导的小鼠死亡率。但人们对 不受控制的细胞因子释放背后的机制基础。虽然有几种潜在的治疗方法可以阻止不同的 目前正在研究炎症细胞因子,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。更好地了解 先天免疫系统识别和响应冠状病毒感染将是关键, 制定治疗策略。此外,特异性先天性免疫传感器、炎性小体 COVID-19疾病发展中的炎症细胞激活和炎症细胞死亡仍然未知。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, 和病原体清除,确定上游传感器和这些途径中的重要分子。在这 我们寻求解开新型先天免疫传感器的基本机制, 我们实验室以前发现的炎性体调节因子,并了解它们与细胞死亡的相互作用 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于理解 先天免疫反应的基本原理根据本建议完成的工作将具有以下特点: 直接感应SARS-CoV-2启动干扰素和炎症反应的主要先天免疫传感器 细胞因子的表达,并确定调节炎症细胞死亡的分子机制, SARS-CoV-2。这些发现有望确定新的信号通路, 通过治疗干预。这些发现不仅适用于COVID-19,也适用于其他传染性疾病。 与过度活跃的先天免疫应答、细胞因子释放和严重的 炎症;这项工作将是根本通知临床方向,以防止发病率和死亡率。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Thirumala-Devi Kanneganti其他文献

Thirumala-Devi Kanneganti的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Thirumala-Devi Kanneganti', 18)}}的其他基金

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
  • 批准号:
    10622511
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
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
  • 批准号:
    10428652
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
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
  • 批准号:
    10311802
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
Innate immune sensors, inflammasomes, and inflammasome-mediated processes in cancer
癌症中的先天免疫传感器、炎症小体和炎症小体介导的过程
  • 批准号:
    10633206
  • 财政年份:
    2020
  • 资助金额:
    $ 39.34万
  • 项目类别:
Innate immune sensors, inflammasomes, and inflammasome-mediated processes in cancer
癌症中的先天免疫传感器、炎症小体和炎症小体介导的过程
  • 批准号:
    10220912
  • 财政年份:
    2020
  • 资助金额:
    $ 39.34万
  • 项目类别:
Innate immune sensors, inflammasomes, and inflammasome-mediated processes in cancer
癌症中的先天免疫传感器、炎症小体和炎症小体介导的过程
  • 批准号:
    10442693
  • 财政年份:
    2020
  • 资助金额:
    $ 39.34万
  • 项目类别:
Innate immune signaling and stress response
先天免疫信号和应激反应
  • 批准号:
    9901240
  • 财政年份:
    2016
  • 资助金额:
    $ 39.34万
  • 项目类别:
The Non-Inflammasome NLRs in Immunity and Host defense
免疫和宿主防御中的非炎性体 NLR
  • 批准号:
    9243972
  • 财政年份:
    2016
  • 资助金额:
    $ 39.34万
  • 项目类别:
Innate immune signaling and stress response
先天免疫信号和应激反应
  • 批准号:
    10327667
  • 财政年份:
    2016
  • 资助金额:
    $ 39.34万
  • 项目类别:
Innate immune signaling and stress response
先天免疫信号和应激反应
  • 批准号:
    10574531
  • 财政年份:
    2016
  • 资助金额:
    $ 39.34万
  • 项目类别:

相似海外基金

Regulation of RIG-I mediated antiviral response upon influenza A virus infection
RIG-I介导的甲型流感病毒感染抗病毒反应的调节
  • 批准号:
    494286
  • 财政年份:
    2023
  • 资助金额:
    $ 39.34万
  • 项目类别:
    Operating Grants
Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
激活 DNA-PK 依赖性抗病毒反应作为一种新型癌症免疫疗法
  • 批准号:
    10364056
  • 财政年份:
    2022
  • 资助金额:
    $ 39.34万
  • 项目类别:
ADAR1-mediated antiviral response in Zika virus (ZIKV) infection
ADAR1 介导的寨卡病毒 (ZIKV) 感染抗病毒反应
  • 批准号:
    10621913
  • 财政年份:
    2022
  • 资助金额:
    $ 39.34万
  • 项目类别:
ADAR1-mediated antiviral response in Zika virus (ZIKV) infection
ADAR1 介导的寨卡病毒 (ZIKV) 感染抗病毒反应
  • 批准号:
    10373627
  • 财政年份:
    2022
  • 资助金额:
    $ 39.34万
  • 项目类别:
Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
激活 DNA-PK 依赖性抗病毒反应作为一种新型癌症免疫疗法
  • 批准号:
    10553146
  • 财政年份:
    2022
  • 资助金额:
    $ 39.34万
  • 项目类别:
Interplay between AMPK and Hippo Signaling Regulates Ocular Antiviral Response to Zika virus infection
AMPK 和 Hippo 信号传导之间的相互作用调节眼部对寨卡病毒感染的抗病毒反应
  • 批准号:
    10322026
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
Mechanisms of IgE-mediated regulation of monocyte antiviral response pathways
IgE介导的单核细胞抗病毒反应途径的调节机制
  • 批准号:
    10640247
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
Mechanisms of IgE-mediated regulation of monocyte antiviral response pathways
IgE 介导的单核细胞抗病毒反应途径调节机制
  • 批准号:
    10438876
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
Antiviral response coupled with transposon derepression in Alzheimer's disease and aging
抗病毒反应与转座子去抑制在阿尔茨海默病和衰老中的作用
  • 批准号:
    10629440
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
Epigenetic Control of Mucosal IRF1/IFN-III Antiviral Response by Enhancer-like Promoter and its Coding lncRNA
增强子样启动子及其编码lncRNA对粘膜IRF1/IFN-III抗病毒反应的表观遗传控制
  • 批准号:
    10373575
  • 财政年份:
    2021
  • 资助金额:
    $ 39.34万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了