Cellular responses to human metapneumovirus infection

细胞对人类偏肺病毒感染的反应

• 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
• 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

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有助于呼吸道病毒感染发病机理的病毒和宿主特异性机制，以开发新的治疗性干预措施以及可行的疫苗候选者。 K22奖将通过提供建立独立调查员职业所需的初步支持来帮助我。人类元瘤病毒（HMPV）是属于paramyxoviridae家族的最近鉴定出的呼吸道病毒。这是儿童呼吸道感染的主要原因。关于HMPV感染的发病机理的信息很少。该建议的目的是通过分子病毒学，细胞生物学和蛋白质化学技术的结合研究宿主细胞对HMPV感染的反应。我最近表明，RNA Helicass-MAVS信号通路在HMPV诱导的免疫和炎症基因的表达中起着重要作用，包括I型干扰素和趋化因子和趋化因子，这些因子和趋化因子通过核因子的激活来调节。 B（NF-？B）和干扰素调节因子（IRF）转录因子。初步研究表明，HMPV糖蛋白G和小的疏水蛋白SH通过可能破坏RIG-I-II和PKA依赖性信号传导来调节HMPV诱导的细胞反应。该建议的目的是确定宿主信号分子和病毒蛋白之间的分子相互作用，并将通过以下特定目的来完成：目标1。定义分子机制，从而抑制rig-l介导的信号传导。在此目标中，我们将通过破坏RIG-I与其下游适配器MAV和/或隔离RIG-I的病毒RNA的关联来研究G蛋白表达是否会干扰RIGI依赖性信号传导。我们还将确定哪些G的残基对于调节HMPV诱导的细胞信号传导很重要。目的2。定义分子机制，从而抑制NF- b激活。在此目标中，我们将首先确定SH抑制NF-磷酸化的机制。然后，我们将绘制残基对其抑制活性至关重要。相关性（请参阅说明）：拟议的研究完成后，我们将获得有关HMPV诱导的细胞信号传导机制的新关键信息，这可能使我们能够专门调节病毒诱导的基因表达，因此可以抗病和先天免疫/炎症反应。从这些研究中获得的结果将有助于开发安全有效的未来HMPV疫苗候选物。

项目成果

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: 10.1016/j.virusres.2013.06.014
• 发表时间: 2013
• 期刊: Virus research
• 影响因子: 5
• 作者: Ren,Junping;Kolli,Deepthi;Deng,Junfang;Fang,Rong;Gong,Bin;Xue,Megan;Casola,Antonella;Garofalo,RobertoP;Garafalo,RobertoP;Wang,Tian;Bao,Xiaoyong
• 通讯作者: Bao,Xiaoyong

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

• DOI: 10.1371/journal.pone.0024496
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ren J;Kolli D;Liu T;Xu R;Garofalo RP;Casola A;Bao X
• 通讯作者: Bao X

Human metapneumovirus infection induces significant changes in small noncoding RNA expression in airway epithelial cells.

• DOI: 10.1038/mtna.2014.18
• 发表时间: 2014-05-20
• 期刊: Molecular therapy. Nucleic acids

A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virus NS1 protein.

人呼吸道合胞病毒 NS1 蛋白抑制干扰素调节因子 3 依赖性基因表达的新机制。

• DOI: 10.1099/vir.0.032987-0
• 发表时间: 2011
• 期刊: The Journal of general virology
• 作者: Ren,Junping;Liu,Tianshuang;Pang,Lan;Li,Kui;Garofalo,RobertoP;Casola,Antonella;Bao,Xiaoyong
• 通讯作者: Bao,Xiaoyong