In vivo Interactions Between a Gamma-Herpesvirus and Innate Immune Responses

γ-疱疹病毒与先天免疫反应之间的体内相互作用

• 批准号: 8660816
• 负责人: REN SUN
• 金额: $ 17.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660816
• 关键词: Achievement; Affect; Animal Model; Attenuated; Benign; Binding; Biological; Biological Models; Collaborations; Complex; Development; Disease; Evolution; Experimental Models; Expression Library; Foundations; Future; Gene Silencing; Genes; Goals; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunologic Surveillance; In Vitro; Incidence; Infection; Interferon Type I; Interferon Type II; Interferons; Kaposi Sarcoma; Knowledge; Lead; Life; Lymphocyte; Malignant Neoplasms; Mediating; Medical; Modeling; Mus; Mutation; Natural Immunity; Open Reading Frames; Pathway interactions; Play; Primates; Proteins; Recombinants; Research; Research Project Grants; Resolution; Role; Signal Transduction; System; Tertiary Protein Structure; Vaccination; Vaccines; Viral; Viral Genes; Viral Proteins; Viral Vaccines; Virus; Wing; Work; adaptive immunity; clinical application; dUTP pyrophosphatase; design; fitness; gammaherpesvirus; immunogenic; immunogenicity; in vivo; in vivo Model; latent infection; member; novel; novel strategies; pre-clinical; primary effusion lymphoma; programs; recombinant virus; recombinant virus vaccine; research study; response; tumor; vaccination strategy; vaccine candidate; vaccine development; virus host interaction

By evading host immune surveillance, herpesviruses can persist in hosts and cause various diseases. Thus, understanding the mechanisms of viral immune evasion is not only essential for developing vaccine approaches to control herpesviral diseases, but also may lead to novel discoveries about the host innate defense system. Of the two wings of the host immune system, innate and adaptive, innate immune responses are very critical for restraining mucosal infection of herpesvirus because they are the first line of defense that profoundly affects the immune control of herpesvirus. Members of the gamma-herpesvirus subfamily are distinct in their ability to establish latent infections in lymphocytes and cause benign or malignant tumors in infected hosts. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is one of two human gamma-herpesviruses and is associated with tumors, such as Kaposi's sarcoma and primary effusion lymphoma. In spite of the viruses' medical importance, the studies of human gamma-herpesvirus infection have been limited mostly to in vitro experiments because of their restricted host range. Therefore, mouse infection by murine gammaherpesvirus68 (MHV-68), which is biologically and genetically related to KSHV-HHV-8, has been used as a small animal model for exploring host-virus interactions during gamma-herpesvirus infection. A MHV-68 ORF expression library was screened, which reveal that three non-essential genes conserved among gamma-herpesviruses, block signaling induced by type I interferons (IFN). Interestingly, all three ORFs share a conserved dUTPase-related domain (DURO), although only one of them possesses enzymatic activity. We propose to characterize these three viral dUTPase-related proteins (DURPs) and the biological significance of their anti-IFN functions. Furthermore, a strategy of inactivating viral anti-IFN genes to generate a live-attenuated virus was explored as a new strategy for vaccination. The proposed research will assess the function of a group of conserved viral proteins, demonstrate the feasibility of the vaccine approach and establish a foundation for future clinical application. Taking a similar approach, this Project 4 will use MHV-68 infection of mice as a model system to assess the biological relevance of the other viral immune evasion genes and virus-host interactions that have been identified in Project 1, 2 and 3, and evaluate their potential utilities in vaccine development.

通过逃避宿主免疫监视，疱疹病毒可以在宿主体内持续存在并引起各种疾病。因此，了解病毒免疫逃避的机制不仅对于开发控制疱疹病毒疾病的疫苗方法至关重要，而且还可能导致关于宿主先天防御系统的新发现。在宿主免疫系统的两个翼中，先天性和适应性，先天性免疫反应对于抑制疱疹病毒的粘膜感染非常关键，因为它们是深刻影响疱疹病毒免疫控制的第一道防线。 γ-疱疹病毒亚科的成员在淋巴细胞中建立潜伏感染并在受感染宿主中引起良性或恶性肿瘤的能力各不相同。卡波西肉瘤相关疱疹病毒 (KSHV/HHV-8) 是两种人类疱疹病毒之一 γ-疱疹病毒，与肿瘤有关，例如卡波西肉瘤和原发性积液 淋巴瘤。尽管病毒具有医学重要性，但由于其宿主范围有限，对人类γ-疱疹病毒感染的研究主要局限于体外实验。因此，小鼠感染鼠伽马疱疹病毒 68 (MHV-68)，其生物学和遗传学与 KSHV-HHV-8 已被用作小动物模型，用于探索 γ-疱疹病毒感染期间宿主与病毒的相互作用。 筛选了 MHV-68 ORF 表达文库，发现 3 个非必需基因保守 在 γ-疱疹病毒中，阻断 I 型干扰素 (IFN) 诱导的信号传导。有趣的是，所有三个 ORF 共享一个保守的 dUTPase 相关结构域 (DURO)，尽管其中只有一个具有酶活性。我们建议表征这三种病毒 dUTPase 相关蛋白 (DURP) 及其抗 IFN 功能的生物学意义。此外，还探索了灭活病毒抗干扰素基因以产生减毒活病毒的策略作为疫苗接种的新策略。拟议的研究将评估一组保守病毒蛋白的功能，证明疫苗方法的可行性，并为未来的临床应用奠定基础。 采用类似的方法，该项目 4 将使用小鼠的 MHV-68 感染作为模型系统来评估 项目1、2和3中已确定的其他病毒免疫逃避基因和病毒-宿主相互作用的生物学相关性，并评估它们在疫苗开发中的潜在效用。