Control of innate immunity and apoptosis by Measles virus P, V and C proteins

麻疹病毒 P、V 和 C 蛋白控制先天免疫和细胞凋亡

• 批准号: 7352405
• 负责人: Patricia DEVAUX
• 金额: $ 15.11万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7352405
• 关键词: Amino Acids; Animal Model; Antiviral Response; Apoptosis; Apoptosis Promoter; Apoptotic; Applications Grants; Area; Attenuated Vaccines; Cells; Cessation of life; Clinical Trials; Cultured Cells; Data; Development; Effectiveness; Equilibrium; Family; Future; Genes; Glioma; Glycine decarboxylase; Goals; Host Defense; Host Defense Mechanism; Immune; Immune response; Immunocompromised Host; Individual; Induction of Apoptosis; Infection; Inflammatory; Interferon Activation; Interferon Type I; Interferons; Laboratories; Lead; Lymphoma; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Measles; Measles virus; Measles virus P protein; Mitochondria; Modeling; Molecular; Molecular Mechanisms of Action; Multiple Myeloma; Mus; Natural Immunity; Oncolytic; Oncolytic viruses; Paramyxovirus; Pathway interactions; Patients; Phosphoproteins; Plasmids; Polymerase; Production; Property; Proteins; Public Health; Research; Role; Signal Pathway; Signal Transduction; Specificity; Stress; System; Testing; Trefoil Motif; Tyrosine; Viral; Virus; Virus Diseases; base; cancer therapy; citrate carrier; cofactor; cytokine; design; domain mapping; improved; inhibitor/antagonist; innovation; killings; protective effect; protein function; receptor; recombinant virus; response; tumor

DESCRIPTION (provided by applicant): Successful viral replication requires not only the efficient production and spread of progeny, but also evasion of host defense mechanisms that limit replication by killing infected cells. Almost all viruses have developed mechanisms to evade host defense, such as interferon (IFN) activation and/or apoptosis induction. Like most viruses, upon infection of cells, measles virus (MV) is subjected to a variety of intracellular antiviral responses. A better understanding of how measles virus evades the host defense mechanisms will facilitate the design of a more attenuated vaccine strain for use in immunosuppressed patients or for the development of new oncolytic viruses for potential cancer therapy. In recent years, it has become clear that protein products from the P gene of viruses within the Paramyxovirus family specifically reduce the effectiveness of the intracellular antiviral responses. The MV P gene encodes for three proteins, the phosphoprotein P, and two accessory proteins V and C. All three proteins have been implicated in innate immune control, but their mechanisms of action still remains unclear. The research proposed here will further characterize the functions of the P gene products in the control of the antiviral response induced by MV. Our study will be conducted using a dual approach that includes a study of the function of the proteins expressed alone as well as in the context of a viral infection. Toward this goal, we have produced expression plasmids encoding for the individual proteins P/V and recombinant viruses deficient in one or both of the V and C proteins and we will characterize their abilities to evade host defense mechanisms. In aim 1, we will characterize the role of a recently identified tyrosine-rich domain in the common region of the P/V protein and assess its importance in the inhibition of IFN signaling. To understand the molecular mechanism of action of this domain, different steps of the IFN signaling pathway will be analyzed and an identification of cellular partners interacting with this domain will be attempted. In aim 2, we will investigate a potential new function for the V and C proteins that consists to protect the cell against induction of apoptosis. We will characterize the apoptotic pathways activated in infected cells in the absence of the V and C proteins. And in a parallel approach we will investigate the protective properties of the V and C proteins against external inducers of apoptosis. The proposed studies are of an important area to understand how measles virus escapes from innate immunity. The proposed research has relevance to public health, as a better understanding of how measles virus evade host defense will facilitate the design of more attenuated vaccine strain for use in immunosuppressed patients or the development of new oncolytic viruses for cancer therapy.

描述（由申请人提供）：成功的病毒复制不仅需要子代的有效产生和传播，还需要逃避通过杀死受感染细胞来限制复制的宿主防御机制。几乎所有病毒都已发展出逃避宿主防御的机制，例如干扰素 (IFN) 激活和/或细胞凋亡诱导。与大多数病毒一样，麻疹病毒 (MV) 在感染细胞后会受到多种细胞内抗病毒反应。更好地了解麻疹病毒如何逃避宿主防御机制将有助于设计一种减毒疫苗株，用于免疫抑制患者或开发用于潜在癌症治疗的新型溶瘤病毒。近年来，人们已经清楚，副粘病毒科病毒 P 基因的蛋白质产物会特异性降低细胞内抗病毒反应的有效性。 MV P 基因编码三种蛋白质：磷蛋白 P 以及两种辅助蛋白 V 和 C。所有三种蛋白质都与先天免疫控制有关，但它们的作用机制仍不清楚。这里提出的研究将进一步表征 P 基因产物在控制 MV 诱导的抗病毒反应中的功能。我们的研究将采用双重方法进行，包括研究单独表达的蛋白质的功能以及在病毒感染的情况下表达的蛋白质的功能。为了实现这一目标，我们生产了编码单个蛋白 P/V 的表达质粒和缺乏 V 和 C 蛋白之一或两者的重组病毒，我们将表征它们逃避宿主防御机制的能力。在目标 1 中，我们将描述最近发现的 P/V 蛋白公共区域中富含酪氨酸的结构域的作用，并评估其在抑制 IFN 信号传导中的重要性。为了了解该结构域的分子作用机制，将分析 IFN 信号传导途径的不同步骤，并尝试鉴定与该结构域相互作用的细胞伙伴。在目标 2 中，我们将研究 V 和 C 蛋白的潜在新功能，即保护细胞免受诱导凋亡。我们将描述在缺乏 V 和 C 蛋白的情况下受感染细胞中激活的凋亡途径的特征。在并行的方法中，我们将研究 V 和 C 蛋白针对外部凋亡诱导剂的保护特性。拟议的研究是了解麻疹病毒如何逃避先天免疫的重要领域。拟议的研究与公共卫生相关，因为更好地了解麻疹病毒如何逃避宿主防御将有助于设计用于免疫抑制患者的减毒疫苗株或开发用于癌症治疗的新型溶瘤病毒。