Regulation of NLRP3 inflammasome activity in response to swine influenza virus infection
NLRP3炎症小体活性对猪流感病毒感染的调节
基本信息
- 批准号:RGPIN-2019-04578
- 负责人:
- 金额:$ 4.23万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2020
- 资助国家:加拿大
- 起止时间:2020-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The inflammasome activity controls production of inflammatory cytokines, which recruit effector cells to the site of infection. Inflammasome is comprised with pattern recognition receptors (PRR), adaptors and effectors. Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) is one of the PRRs, together with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) and procaspase-1, the NLRP3 forms a cytosolic protein complex called NLRP3 inflammasome which plays a pivotal role in modulating lung inflammation in response to influenza A virus (IAV) infection. Our previous study showed swine influenza virus (IAV-S) infection induced NLRP3 inflammasome-mediated IL-1 production in primary porcine alveolar macrophages (PAMs) and the IL-1 level is associated with lung pathology. However, how IAV-S activates and modulates NLRP3 and how NLRP3 inflammasome contributes to the host immunity upon IAV-S infection in pigs remain elusive.
The long-term objective of my NSERC supported research program is to understand the regulation of innate immune responses upon IAV-S infection in pigs. The short-term objective during this 5-year term is to understand porcine NLPR3 inflammasome activation and regulation upon IAV-S infection and its role in IAV-S pathogenesis in pigs.
I propose three specific aims:
1) To elucidate the molecular mechanisms by which NLRP3 inflammasome is activated and regulated by cellular factors upon IAV-S infection. We will test the hypothesis that IAV-S infection of PAMs induces phosphorylation of dynamin-related protein 1 (DRP1) by a cellular kinase RIPK1 (receptor-interacting protein kinase 1), resulting in mitochondria fission. Release of reactive oxygen species (ROS) from mitochondria fission leads to the activation of NLPR3 inflammasome.
2) To understand how NLRP3 inflammasome is activated and regulated by viral factors. We ask how viral protein PB1-F2 activates NLRP3 inflammasome through changing mitochondria dynamic; and how viral NS1 protein regulates inflammasome activity through post-translational modifications on NLRP3 and ASC. Mutant viruses carrying mutations in PB1-F2 or NS1 will be generated by reverse genetics. Their ability to activate inflammasome will be tested.
3) To examine the contribution of NLRP3 inflammasome to IAV-S pathogenesis in pigs. We will study what immune cells are recruited to the pig lung in response to IAV-S infection; and the NLRP3 inflammasome activation kinetics in immune cells. Pathogenesis of mutant viruses with different ability to activate NLRP3 inflammasome will be evaluated in pigs.
Significance: A balanced inflammasome activation level is believed to be beneficial to the host to combat virus infection. The research will gain the fundamental knowledge on the mechanisms underlying IAV-S induced inflammasome activation and regulation in pigs. The knowledge will eventually contribute to a better control of swine influenza in pigs.
炎性小体活性控制炎性细胞因子的产生,其将效应细胞募集到感染部位。炎性小体由模式识别受体、衔接子和效应子组成。含核苷酸结合结构域和富含亮氨酸重复序列的蛋白3(NLRP 3)是PRR之一,它与包含半胱天冬酶募集结构域(ASC)和半胱天冬酶原-1(procaspase-1)的肺水肿相关斑点样蛋白(speck-like protein,speck-like protein,speck-like protein)一起形成称为NLRP 3炎性体的胞质蛋白复合物,在调节甲型流感病毒(IAV)感染后的肺部炎症反应中起关键作用。我们的前期研究表明猪流感病毒(IAV-S)感染可诱导原代猪肺泡巨噬细胞(PAM)产生NLRP 3炎性体介导的IL-1,且IL-1水平与肺病理相关。然而,IAV-S如何激活和调节NLRP 3以及NLRP 3炎性体如何在IAV-S感染猪后促进宿主免疫仍然是未知的。
我的NSERC支持的研究项目的长期目标是了解猪感染IAV-S后先天免疫应答的调节。在这5年期间的短期目标是了解猪NLPR 3炎性小体在IAV-S感染后的激活和调节及其在猪IAV-S发病机制中的作用。
我提出三个具体目标:
1)目的:阐明IAV-S感染后NLRP 3炎性体被细胞因子激活和调控的分子机制。我们将检验IAV-S感染PAM诱导细胞激酶RIPK 1(受体相互作用蛋白激酶1)磷酸化动力蛋白相关蛋白1(DRP 1),导致线粒体分裂的假设。线粒体分裂释放的活性氧(ROS)导致NLPR 3炎性体的活化。
2)了解NLRP 3炎性体是如何被病毒因子激活和调节的。 我们问病毒蛋白PB 1-F2如何通过改变线粒体动力学激活NLRP 3炎性小体;以及病毒NS 1蛋白如何通过对NLRP 3和ASC的翻译后修饰调节炎性小体活性。将通过反向遗传学产生携带PB 1-F2或NS 1突变的突变病毒。他们激活炎性小体的能力将被测试。
3)研究NLRP 3炎性体在猪IAV-S发病机制中的作用。我们将研究什么样的免疫细胞被招募到猪肺中以响应IAV-S感染;以及免疫细胞中的NLRP 3炎性小体激活动力学。 将在猪中评价具有不同激活NLRP 3炎性体能力的突变病毒的发病机制。
意义:平衡的炎性小体激活水平被认为有利于宿主对抗病毒感染。本研究为深入了解IAV-S诱导猪炎症小体的激活和调控机制奠定了基础。这些知识最终将有助于更好地控制猪流感。
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)
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Zhou, Yan其他文献
Morphology-based deep learning enables accurate detection of senescence in mesenchymal stem cell cultures.
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10.1186/s12915-023-01780-2 - 发表时间:
2024-01-02 - 期刊:
- 影响因子:5.4
- 作者:
He, Liangge;Li, Mingzhu;Wang, Xinglie;Wu, Xiaoyan;Yue, Guanghui;Wang, Tianfu;Zhou, Yan;Lei, Baiying;Zhou, Guangqian - 通讯作者:
Zhou, Guangqian
Current status and training needs of trainee anesthesiologists in lung transplantation anesthesia in China: A single-center survey.
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10.1016/j.heliyon.2022.e12428 - 发表时间:
2022-12 - 期刊:
- 影响因子:4
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Zhou, Yan;Qin, Zhong;Wang, Guilong;Chen, Wenyi;Zhang, Xin - 通讯作者:
Zhang, Xin
Molecular, Biological and Phylogenetic Analysis of Chinese Isolates of Hop stunt viroid Associated with Citrus Cachexia Disease
- DOI:
10.1111/j.1439-0434.2009.01629.x - 发表时间:
2010-05-01 - 期刊:
- 影响因子:1.5
- 作者:
Wang, Xuefeng;Zhou, Yan;Zhou, Changyong - 通讯作者:
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XPS, UV-vis spectroscopy and AFM studies on removal mechanisms of Si-face SiC wafer chemical mechanical polishing (CMP)
XPS、紫外可见光谱和 AFM 研究 Si 面 SiC 晶圆化学机械抛光 (CMP) 去除机理
- DOI:
10.1016/j.apsusc.2014.08.011 - 发表时间:
2014-10-15 - 期刊:
- 影响因子:6.7
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Zhou, Yan;Pan, Guoshun;Luo, Guihai - 通讯作者:
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Effects of acupuncture on cartilage p38MAPK and mitochondrial pathways in animal model of knee osteoarthritis: A systematic evaluation and meta-analysis.
针灸对膝盖骨关节炎动物模型软骨p38mapk和线粒体途径的影响:系统评估和荟萃分析。
- DOI:
10.3389/fnins.2022.1098311 - 发表时间:
2022 - 期刊:
- 影响因子:4.3
- 作者:
Ye, Jiang-nan;Su, Cheng-guo;Jiang, Yu-qing;Zhou, Yan;Sun, Wen-xi;Zheng, Xiao-xia;Miao, Jin-tao;Li, Xiang-yue;Zhu, Jun - 通讯作者:
Zhu, Jun
Zhou, Yan的其他文献
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{{ truncateString('Zhou, Yan', 18)}}的其他基金
Regulation of NLRP3 inflammasome activity in response to swine influenza virus infection
NLRP3炎症小体活性对猪流感病毒感染的调节
- 批准号:
RGPIN-2019-04578 - 财政年份:2022
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Regulation of NLRP3 inflammasome activity in response to swine influenza virus infection
NLRP3炎症小体活性对猪流感病毒感染的调节
- 批准号:
RGPIN-2019-04578 - 财政年份:2021
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Regulation of NLRP3 inflammasome activity in response to swine influenza virus infection
NLRP3炎症小体活性对猪流感病毒感染的调节
- 批准号:
RGPIN-2019-04578 - 财政年份:2019
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2018
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2017
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2016
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2015
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2014
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2013
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Innate immunity to swine influenza virus in its natural host
天然宿主对猪流感病毒具有先天免疫力
- 批准号:
298312-2011 - 财政年份:2012
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
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相似海外基金
Regulation of NLRP3 inflammasome activity in response to swine influenza virus infection
NLRP3炎症小体活性对猪流感病毒感染的调节
- 批准号:
RGPIN-2019-04578 - 财政年份:2022
- 资助金额:
$ 4.23万 - 项目类别:
Discovery Grants Program - Individual
Regulation of NLRP3 inflammasome activity in response to swine influenza virus infection
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