Project 1 - Virus-Host Interactions in Gammaherpesvirus Pathogenesis

项目 1 - 伽玛疱疹病毒发病机制中的病毒-宿主相互作用

• 批准号: 8652484
• 负责人: James Craig Forrest
• 金额: $ 32.95万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8652484
• 关键词: Address; Adult; Animal Model; Antiviral Agents; Antiviral Response; Antiviral Therapy; Bone Marrow; Burkitt Lymphoma; Cells; Centers of Research Excellence; Chimera organism; Chronic; Communicable Diseases; Complement; DNA Binding; DNA Tumor Viruses; Data; Disease; Evaluation; Foundations; Funding; Genetic Transcription; Health; Hodgkin Disease; Host Defense Mechanism; Human; Human Herpesvirus 4; Human Herpesvirus 8; IFNAR1 gene; IRF3 gene; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory Response; Interferon-alpha; Interferon-beta; Interferons; Lung; Lymphocyte; Malignant Neoplasms; Mediating; Mucous Membrane; Mus; Nature; Pathogenesis; Pathway interactions; Persons; Production; Proteins; Publishing; Recombinants; Repressor Proteins; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Solid; System; Testing; Transcript; Transcription Repressor/Corepressor; Transcriptional Regulation; Viral; Viral Genes; Viral Proteins; Virulence Factors; Virus; Virus Diseases; Wild Type Mouse; Work; antigen binding; base; cancer risk; cell type; cellular targeting; gammaherpesvirus; gene function; gene repression; human IRF3 protein; immune activation; in vivo; interferon regulatory factor-3; latency-associated nuclear antigen; microbial; mutant; novel; pathogen; research study; success; tissue culture; transcription factor; type I interferon receptor; virus host interaction

The human gammaherpesviruses (GHVs) Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are DNA tumor viruses that establish lifelong chronic infections of host lymphocytes and other cell types. Through the expression of viral gene products that alter normal cellular signaling pathways and counteract host immune responses, GHVs place the chronically infected host at risk for numerous malignancies. As it relates to the COBRE theme of defining the impact of microbial virulence factors on host inflammatory and immune responses, the overall objective of experiments described in this project is to better define mechanisms by which GHVs counteract innate host defense mechanisms in order to successfully colonize a host. Central to this objective is the utilization of murine gammaherpesvirus-68 (MHV68), a naturally occurring rodent pathogen that is genetically related to EBV and KSHV and recapitulates key aspects of human GHV infection as a tractable small-animal model to define the virus-host interaction in vivo. Extending our published and preliminary data, the current proposal specifically seeks to understand functions of the MHV68 latency-associated nuclear antigen (mLANA), a putative viral transcriptional repressor protein, as a critical modulator of antiviral transcriptional pathways or cellular immune responses activated by interferon alpha/Beta (IFN-I) signaling that would otherwise restrict GHV infection. This work will be accomplished in three integrated but independent specific aims: (1) define IFN-l-mediated control of GHV infection at mucosal barriers, (2) elucidate roles for mLANA-mediated transcriptional control in MHV68 pathogenesis, and (3) define mLANA-interferon regulatory factor 3 (IRF-3) interactions in MHV68 infection. The proposed experiments hold broad significance by addressing two critical gaps in our understanding of GHV pathogenesis: the functions of viral disease determinants in the success of GHV infection and the interactions of GHV with host innate immune response pathways. Moreover, by advancing understanding of the nature of host immune responses, which is fundamentally important to all infectious diseases, the proposed experiments may also hold relevance for diseases caused by diverse and unrelated intracellular pathogens.

人类γ疱疹病毒（GHV）、EB病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV）是DNA肿瘤病毒，其建立宿主淋巴细胞和其他细胞类型的终身慢性感染。通过病毒基因产物的表达，改变正常的细胞信号传导途径和抵消宿主的免疫反应，GHV将慢性感染的宿主置于许多恶性肿瘤的风险中。由于它涉及到定义微生物毒力因子对宿主炎症和免疫反应的影响的COBRE主题，本项目中描述的实验的总体目标是更好地定义GHV抵消先天宿主防御机制的机制，以便成功地定殖宿主。这一目标的核心是利用鼠γ疱疹病毒-68（MHV 68），一种天然存在的啮齿动物病原体，与EBV和KSHV遗传相关，并概括了人类GHV感染的关键方面，作为一种易于处理的小动物模型，以确定体内病毒-宿主相互作用。扩展我们已发表的和初步的数据，目前的建议，特别是寻求了解功能的MHV 68潜伏相关的核抗原（mLANA），一个假定的病毒转录抑制蛋白，作为抗病毒转录途径或细胞免疫反应的关键调制器激活的干扰素α/β（IFN-I）信号，否则会限制GHV感染。这项工作将在三个整合但独立的具体目标中完成：（1）定义IFN-1介导的对粘膜屏障处GHV感染的控制，（2）阐明mLANA介导的转录控制在MHV 68发病机制中的作用，和（3）定义mLANA-干扰素调节因子3（IRF-3）在MHV 68感染中的相互作用。拟议的实验具有广泛的意义，通过解决我们对GHV发病机制的理解中的两个关键差距：病毒疾病决定因素在GHV感染成功中的作用以及GHV与宿主先天免疫应答途径的相互作用。此外，通过推进对宿主免疫反应性质的理解，这对所有感染性疾病都至关重要，所提出的实验也可能与由不同和不相关的细胞内病原体引起的疾病相关。