Host innate immune response induction and shutoff during poxvirus infection

痘病毒感染期间宿主先天免疫反应的诱导和关闭

• 批准号: 8774340
• 负责人: Zhilong Yang
• 金额: $ 24.9万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-18 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774340
• 关键词: Affect; Animal Diseases; Antiviral Agents; Antiviral Response; Apoptosis; Basic Science; Biological; Biology; Cancer Vaccines; Categories; Cell Death; Cell Survival; Cells; Clinical Research; Communicable Diseases; Communication; Cultured Cells; Cytokine Signaling; DNA biosynthesis; Dendritic Cells; Development; Discipline; Doctor of Philosophy; Down-Regulation; Engineering; Environment; Family; Fibroblasts; Flavivirus; Fostering; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Grant; HIV; Hela Cells; Herpesviridae; Host Defense; Human; Human Herpesvirus 8; Hypersensitivity; Immune; Immune response; Immunologic Receptors; Immunology; Infection; Infectious Disease Immunology; Inflammatory; Inflammatory Response; Interleukin-6; Intramural Research; Intramural Research Program; Laboratories; Lead; Life; Lytic; Malignant Neoplasms; Manuscripts; Mediating; Mentors; Messenger RNA; Minority; Monkeypox; Mosses; NF-kappa B; National Institute of Allergy and Infectious Disease; Occupations; Outcome; Papillomavirus; Pathway interactions; Phase; Play; Postdoctoral Fellow; Poxviridae; Poxviridae Infections; Principal Investigator; Protein Biosynthesis; RNA Sequences; Research; Research Personnel; Resources; Role; Shapes; Signal Pathway; Signal Transduction; Smallpox; Staging; Students; Techniques; Time; Training; Translating; United States National Institutes of Health; Vaccines; Vaccinia virus; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Wood material; Work; Writing; Zoonoses; base; career; career development; cell type; cytokine; design; experience; expression vector; genome-wide; human disease; improved; influenzavirus; innovation; interest; macrophage; member; next generation sequencing; novel strategies; pathogen; poxvirus vectors; prevent; programs; prototype; reactivation from latency; receptor; response; skills; tool; tool development; vaccine development; vector vaccine; vector-based vaccine; viral DNA; virus host interaction; virus infection mechanism; weapons

DESCRIPTION (provided by applicant): My long-term career goal is to establish a productive basic science research group to understand the biology of viral pathogens and their infected hosts, ultimately translating the findings towards the development of strategies to treat or prevent viral diseases. The short-term career goal is to develop the essential expertise and skills to foster my transition from a postdoctoral trainee to an independent investigator. In the laboratory of Dr. Charles Wood as a PhD student, I conducted studies to decipher the mechanism of viral and cellular factors involved in Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation from latency. In the laboratory of Dr. Bernard Moss, I employed high-throughput next-generation sequencing technique and other approaches to investigate poxvirus gene expression and the host interaction in a genome-wide scale. These experiences allowed me to develop expertise necessary for my proposed studies. Environment: The NIH Intramural Research Program offers both strong well-established research programs and rich resources for career development of postdoctoral fellows. The NIAID Division of Intramural Research (DIR) conducts basic and clinical research in a broad range of disciplines related to allergy, immunology and infectious diseases. The Laboratory of Viral Diseases has seven nationally and internationally recognized principal investigators that carry out cutting edge research on poxvirus, HIV, influenza virus, herpesvirus, flavivirus and papilloma virus. The mentor, Dr. Bernard Moss is a prominent poxvirologist with significant contributions in nearly all aspects of poxvirus research and has trained many principal investigators in his career. I will take the advantages of the NIH and Dr. Moss's laboratory to enhance my intellectual background in immunology, develop expertise necessary for conducting the proposed study and improve my skills on scientific communication, manuscript- and grant-writing, lab management, job search and expand the scope of my research. Research: Poxviruses can cause deadly human and animal diseases, such as smallpox and monkeypox and have the potential to be used as biological weapons. They are also extensively used as expression vectors for vaccine development. Virus-host interaction during the host innate immune response plays a crucial role in shaping the outcome of viral infection. My previous work on the simultaneous profiling the transcriptomes of vaccinia virus (the prototype poxvirus) and its infected host has shown that a small group of cellular mRNAs was increased at the early time of vaccinia virus infection before viral DNA replication, suggesting specific host response to virus. The upregulated mRNAs are enriched for genes involved in the innate immune response, including inflammatory cytokines, particularly those in the IL-6 family. However, during the post DNA replication stage of vaccinia virus infection, vaccinia virus induced the downregulation of host mRNAs, termed host shutoff, including many genes involved in the innate immune response and those genes were upregulated at the early stage. The goal of this proposal is to understand the induction and shutoff of the host innate immune response during poxvirus infection with a specific focus on inflammatory response. I hypothesize that while vaccinia virus induces a rapid host innate immune response, particularly the inflammatory response, before viral DNA replication, the host shutoff during the post DNA replication stage provides a potent mechanism to blunt host antiviral innate immune responses. In Specific Aim 1, I will identify host antiviral innate immune genes induced by VACV infection and the mechanisms of IL-6 family cytokine induction in response to VACV infection. In Specific Aim 2, I will determine the effect of the host shutoff on the antiviral innate response to VACV infection. Finally, in Specific Aim 3, I will determine the role of IL-6 family cytokines and signaling during VACV replication. Completion of the study will advance the understanding of poxvirus-host interactions, and may ultimately lead to the development of safer and more effective poxvirus vectors and novel strategies to prevent poxvirus infection.

描述（由申请人提供）：我的长期职业目标是建立一个有效的基础科学研究小组，以了解病毒病原体及其感染宿主的生物学，最终将发现转化为制定治疗或预防病毒疾病的策略。短期职业目标是发展基本的专业知识和技能，以促进我从博士后学员到独立调查员的过渡。在查尔斯·伍德博士（Charles Wood）的实验室中，我进行了研究，研究了与潜伏期中肉瘤相关的疱疹病毒（KSHV）裂解裂解的病毒和细胞因子的机制。在伯纳德·莫斯（Bernard Moss）博士的实验室中，我采用了高通量的下一代测序技术和其他方法来研究痘病毒基因表达和宿主的相互作用，并以全基因组范围的范围进行了研究。这些经验使我能够发展为我提出的研究所需的专业知识。环境：NIH壁内研究计划既为博士后研究员的职业发展提供了强大的知名研究计划和丰富的资源。壁内研究（DIR）的NIAID划分在与过敏，免疫学和传染病有关的广泛学科中进行基础和临床研究。病毒疾病的实验室在国内和国际公认的主要研究人员中进行了七名，他们对Poxvirus，HIV，HIV，流感病毒，疱疹病毒，Flavivivirus和Papilloma病毒进行了尖端研究。这位导师伯纳德·莫斯（Bernard Moss）博士是一位杰出的毒病医生，在Poxvirus Research的几乎所有方面都有重要的贡献，并在其职业生涯中培训了许多主要研究人员。我将利用NIH和MOSS博士的实验室的优势来增强我的免疫学智力背景，开发进行拟议的研究所必需的专业知识，并提高我在科学沟通，手稿和授予写作，实验室管理，求职，求职和扩大我的研究范围上的技能。研究：痘病毒会引起致命的人类和动物疾病，例如天花和蒙基托克斯，并有可能被用作生物武器。它们还广泛用作疫苗发育的表达向量。宿主先天免疫反应期间的病毒宿主相互作用在塑造病毒感染的结果中起着至关重要的作用。我以前关于同时分析疫苗病毒（原型痘病毒）及其感染宿主的转录组的工作表明，在病毒DNA复制之前疫苗病毒感染的早期，一小组细胞mRNA增加了，提出了对病毒的特定宿主反应。上调的mRNA富含参与先天免疫反应的基因，包括炎症细胞因子，尤其是IL-6家族中的细胞因子。然而，在疫苗病毒感染的DNA后复制阶段，离甲酸病毒诱导了宿主mRNA的下调，称为宿主关闭，其中包括与先天免疫反应有关的许多基因，这些基因在早期阶段被上调。该提案的目的是了解孢子病毒感染期间宿主先天免疫反应的诱导和关闭，特别关注炎症反应。我假设，虽然Vaccinia病毒在病毒DNA复制之前诱导了快速的宿主先天免疫反应，尤其是炎症反应，但在DNA后复制阶段的宿主关闭阶段为钝性宿主抗病毒抗病毒抗病毒抗病毒抗病毒抗病性免疫反应提供了有效的机制。在特定目标1中，我将确定VACV感染诱导的宿主抗病毒药性抗病毒先天免疫基因以及IL-6家族细胞因子诱导的机制对VEVV感染的响应。在特定的目标2中，我将确定宿主关闭对VAVV感染的先天反应的影响。最后，在特定的目标3中，我将确定IL-6家族细胞因子和VACV复制过程中信号传导的作用。这项研究的完成将提高对痘病毒 - 宿主相互作用的理解，并最终导致开发更安全，更有效的蛇毒载体以及防止痘病毒感染的新型策略。