Cellular responses to human metapneumovirus infection

细胞对人类偏肺病毒感染的反应

基本信息

批准号：
8137253
负责人：
Xiaoyong Bao
金额：
$ 10.8万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8137253
关键词：
Accounting Acetylation Affect Antiviral Agents Antiviral Response Binding Cellular biology Child Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Epidemic Epithelial Cells Event Family Future GTP-Binding Proteins Gene Expression Genes Genetic Transcription Goals Hospitalization Host Defense Human Metapneumovirus Immune Immune response In Vitro Infection Inflammatory Inflammatory Response Instruction Interferon Type I Interferons Investigation K22 Award Maps Mediating Molecular Molecular Virology National Institute of Allergy and Infectious Disease Nuclear Paramyxoviridae Pathogenesis Phosphorylation Play Positioning Attribute Post-Translational Protein Processing Principal Investigator Protein Chemistry Protein Kinase A Inhibitor Proteins RNA Helicase Reagent Research Research Personnel Respiratory Tract Infections Respiratory syncytial virus Role Serine Signal Pathway Signal Transduction Signaling Molecule System Techniques Testing Transcription Factor AP-1 Tretinoin Vaccines Viral Viral Proteins Virus Virus Diseases base career chemokine glycoprotein G human metapneumovirus G glycoprotein in vitro activity novel therapeutic intervention older patient pathogen protein expression protein kinase A kinase recombinant virus research study respiratory respiratory virus response transcription factor vaccine candidate viral RNA

项目摘要

DESCRIPTION (provided by applicant): My long-term career goal is to investigate viral- and host-specific mechanisms that contribute to the pathogenesis of respiratory viral infections, in order to develop novel therapeutic intervention, as well as viable vaccine candidates. The K22 award will help me by providing the initial support necessary to establish a career as an independent investigator. Human metapneumovirus (hMPV) is a recently identified respiratory virus belonging to the Paramyxoviridae family. It is a leading cause of respiratory infections in children. Little information is available regarding the pathogenesis of hMPV infection. The aim of this proposal is to investigate host cellular responses to hMPV infection using a combination of molecular virology, cellular biology and protein chemistry techniques. I have recently shown that the RNA helicases-MAVS signaling pathway plays a significant role in hMPV-induced expression of immune and inflammatory genes, including type I interferon and chemokines, which are regulated through the activation of Nuclear Factor-? B (NF-?B) and Interferon Regulatory Factors (IRF) transcription factors. Preliminary studies demonstrated that hMPV glycoprotein G and small hydrophobic protein SH modulate hMPV-induced cellular responses by likely disrupting RIG-I- and PKA-dependent signaling. The goal of this proposal is to identify molecular interaction between host signaling molecules and viral proteins and will be accomplished through the following specific aims: Aim 1. To define the molecular mechanism whereby G inhibits RIG-l-mediated signaling. In this aim, we will investigate whether G protein expression interferes with RIG-I dependent signaling by disrupting the association of RIG-I with its downstream adaptor MAVS and/or by sequestering viral RNA from RIG-I. We will also identify which residues of G are important for modulating hMPV-induced cellular signaling. Aim 2. To define the molecular mechanism whereby SH inhibits NF-?B activation. In this aim, we will first determine the mechanism by which SH inhibits NF-?B phosphorylation. We will then map SH residue(s) critical for its inhibitory activity. RELEVANCE (See instructions): Upon completion of the proposed studies, we will obtain new critical information on the mechanisms of hMPV-induced cellular signaling, which may allow us to specifically modulate viral-induced gene expression and therefore antiviral and innate immune/inflammatory responses. The results obtained from these studies will be instrumental for the development of future hMPV vaccine candidates which are safe and effective.

描述（由申请人提供）：我的长期职业目标是研究导致呼吸道病毒感染发病机制的病毒和宿主特异性机制，以开发新的治疗干预措施以及可行的候选疫苗。 K22 奖将帮助我提供建立独立调查员职业生涯所需的初步支持。人类偏肺病毒（hMPV）是最近发现的一种呼吸道病毒，属于副粘病毒科。它是儿童呼吸道感染的主要原因。关于 hMPV 感染发病机制的信息很少。该提案的目的是结合分子病毒学、细胞生物学和蛋白质化学技术来研究宿主细胞对 hMPV 感染的反应。我最近发现RNA解旋酶-MAVS信号通路在hMPV诱导的免疫和炎症基因表达中发挥着重要作用，包括I型干扰素和趋化因子，这些基因通过核因子-α的激活进行调节。 B (NF-κB) 和干扰素调节因子 (IRF) 转录因子。初步研究表明，hMPV 糖蛋白 G 和小疏水蛋白 SH 可能通过破坏 RIG-I 和 PKA 依赖性信号传导来调节 hMPV 诱导的细胞反应。本提案的目标是确定宿主信号分子和病毒蛋白之间的分子相互作用，并将通过以下具体目标来实现：目标 1. 确定 G 抑制 RIG-1 介导的信号传导的分子机制。为此，我们将研究 G 蛋白表达是否通过破坏 RIG-I 与其下游接头 MAVS 的关联和/或通过从 RIG-I 中隔离病毒 RNA 来干扰 RIG-I 依赖性信号传导。我们还将确定 G 的哪些残基对于调节 hMPV 诱导的细胞信号传导很重要。目标 2. 明确 SH 抑制 NF-κB 激活的分子机制。为此，我们首先确定SH抑制NF-κB磷酸化的机制。然后我们将绘制对其抑制活性至关重要的 SH 残基图谱。相关性（参见说明）：完成拟议的研究后，我们将获得有关 hMPV 诱导的细胞信号传导机制的新的关键信息，这可能使我们能够特异性调节病毒诱导的基因表达，从而调节抗病毒和先天免疫/炎症反应。这些研究获得的结果将有助于开发未来安全有效的 hMPV 候选疫苗。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MyD88 controls human metapneumovirus-induced pulmonary immune responses and disease pathogenesis.

MyD88 控制人类偏肺病毒诱导的肺部免疫反应和疾病发病机制。

DOI：
发表时间：
2013-09
期刊：
影响因子：
5
作者：
Ren, Junping;Kolli, Deepthi;Deng, Junfang;Fang, Rong;Gong, Bin;Xue, Megan;Casola, Antonella;Garofalo, Roberto P;Garafalo, Roberto P;Wang, Tian;Bao, Xiaoyong
通讯作者：
Bao, Xiaoyong

Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection.

DOI：
10.1038/mt.2012.237
发表时间：
2013-02-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Qingrong Wang;Inhan Lee;Junping Ren;S. Ajay;Yong Sun Lee;X. Bao
通讯作者：
X. Bao

Human metapneumovirus inhibits IFN-β signaling by downregulating Jak1 and Tyk2 cellular levels.

人类偏肺病毒通过下调 Jak1 和 Tyk2 细胞水平来抑制 IFN-β 信号传导。

DOI：
发表时间：
2011
期刊：
影响因子：
3.7
作者：
Ren, Junping;Kolli, Deepthi;Liu, Tianshuang;Xu, Renling;Garofalo, Roberto P;Casola, Antonella;Bao, Xiaoyong
通讯作者：
Bao, Xiaoyong

Human metapneumovirus M 2-2 protein inhibits innate cellular signaling by targeting MAVS 1 2

人偏肺病毒 M 2-2 蛋白通过靶向 MAVS 1 2 抑制先天细胞信号传导