Regulators of Innate Immune Responses to Gamma-herpesviruses

针对微生物入侵的前线防御是病原体相关分子模式（PAMP）的受体介导的识别，其触发导致诱导起始先天免疫应答（包括1型干扰素的分泌）的信号级联。病原体衍生的核酸，包括DNA，作为可以触发这种反应的有效PAMP起作用，并且被TLR 9、DAI/RNA聚合酶III和可能的另外的DNA敏感受体识别。鼠γ疱疹病毒68（MHV-68）与人类疱疹病毒8（HHV 8）密切相关，也称为卡波西肉瘤相关疱疹病毒（KSHV），是卡波西肉瘤的病原体。这些病毒含有双链DNA基因组，研究表明它们可能引起TLR 9依赖性和TLR 9非依赖性抗病毒反应。在这项研究中，我们建议利用系统水平的数据来阐明信号网络和宿主-病原体相互作用，这些相互作用构成了对γ疱疹病毒的先天免疫反应的基础。为此，我们使用了多种方法来系统地生成针对疱疹病毒的病毒宿主蛋白质-蛋白质相互作用图谱。我们假设这些相互作用的一个子集是病毒逃避先天反应的基础。在本提案中，我们将描述宿主分子复合物的特征，这些复合物已被实验定义为位于HHV 8宿主-病原体相互作用和先天免疫反应的界面。Chanda博士在功能基因组学、先天免疫信号传导和哺乳动物细胞遗传分析方面拥有10多年的经验，Krogan博士在大规模蛋白质组学和网络分析领域拥有10多年的经验。这些研究 有望为调控γ疱疹病毒感染早期免疫反应的细胞和病毒过程提供全面的分子见解，并将为HHVB新型疫苗和佐剂的开发奠定基础

A front line defense against microbial invasion is the receptor-mediated recognition of pathogen-associated molecular patterns (PAMPs), which triggers a signaling cascade that results in the induction of initiate innate immune responses, including the secretion of Type-1 interferons. Pathogen-derived nucleic acids, including DNA, function as potent PAMPs that can trigger this response, and are recognized by TLR9, DAI/RNA polymerase Ill, and likely additional DNA-sensing receptors. Murine Gammaherpesvirus 68 (MHV-68) is closely related to human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), which is the causative agent of Kaposi's sarcoma. These viruses contain double stranded DNA genomes, and studies indicate that they likely elicit both TLR9-dependent and TLR9- independent antiviral responses. In this study, we propose to leverage systems-level data to elucidate signaling networks and host-pathogen interactions that form the basis of innate immune responses to gammaherpesviruses. To this end, we have used a variety of methods to systematically generate viral¿ host protein-protein interaction maps targeting herpesviruses. We hypothesize that a subset of these interactions underlies viral evasion of innate responses. In this proposal, we will characterize host molecular complex that have been experimentally defined to lie at the interface of HHV8 host-pathogen interactions and innate immune responses. Dr. Chanda has over 10 years experience in functional genomics, innate immune signaling, and genetic analysis in mammalian cells, and Dr. Krogan brings over 10 years of experience in the areas of large-scale proteomic and network analysis. These studies are expected to provide global molecular insight into cellular and viral processes that regulate early immune responses to gammaherpesvirus infection, and will be fundamental towards the development of novel vaccines and adjuvants for HHVB