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富有成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，最终将研究结果转化为治疗或预防病毒性疾病的策略的制定。短期职业目标是培养必要的专业知识和技能，以促进我从博士后实习生向独立研究者的转变。作为一名博士生，我在 Charles Wood 博士的实验室进行了研究，以破译参与卡波西肉瘤相关疱疹病毒 (KSHV) 潜伏期裂解再激活的病毒和细胞因子的机制。在 Bernard Moss 博士的实验室中，我采用高通量下一代测序技术和其他方法在全基因组范围内研究痘病毒基因表达和宿主相互作用。这些经历使我能够培养我拟议的研究所需的专业知识。环境：NIH 校内研究项目为博士后研究员的职业发展提供了强大而完善的研究项目和丰富的资源。 NIAID 校内研究部 (DIR) 在过敏、免疫学和传染病相关的广泛学科领域开展基础和临床研究。病毒病实验室拥有七名国内外公认的主要研究人员，对痘病毒、艾滋病毒、流感病毒、疱疹病毒、黄病毒和乳头状瘤病毒进行前沿研究。导师 Bernard Moss 博士是一位著名的痘病毒学家，在痘病毒研究的几乎所有方面都做出了重大贡献，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 博士实验室的优势，增强我在免疫学方面的知识背景，培养进行拟议研究所需的专业知识，并提高我在科学交流、手稿和拨款写作、实验室管理、求职和研究方面的技能。扩大我的研究范围。研究：痘病毒可引起致命的人类和动物疾病，例如天花和猴痘，并有可能用作生物武器。它们还广泛用作疫苗开发的表达载体。宿主先天免疫反应期间病毒与宿主的相互作用在塑造病毒感染的结果中起着至关重要的作用。我之前对痘苗病毒（原型痘病毒）及其感染宿主的转录组进行同步分析的工作表明，在痘苗病毒感染的早期，在病毒 DNA 复制之前，一小群细胞 mRNA 有所增加，这表明宿主对痘苗病毒的特异性反应病毒。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 家族的细胞因子。然而，在痘苗病毒感染的DNA复制后阶段，痘苗病毒诱导宿主mRNA下调，称为宿主关闭，包括许多参与先天免疫反应的基因，这些基因在早期就被上调。该提案的目标是了解痘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。我推测，虽然牛痘病毒在病毒 DNA 复制之前诱导快速的宿主先天免疫反应，特别是炎症反应，但 DNA 复制后阶段的宿主关闭提供了一种有效的机制来削弱宿主抗病毒先天免疫反应。在具体目标 1 中，我将鉴定 VACV 感染诱导的宿主抗病毒先天免疫基因以及响应 VACV 感染的 IL-6 家族细胞因子诱导机制。在具体目标 2 中，我将确定宿主关闭对 VACV 感染的抗病毒先天反应的影响。最后，在具体目标 3 中，我将确定 IL-6 家族细胞因子和信号在 VACV 复制过程中的作用。该研究的完成将增进对痘病毒与宿主相互作用的了解，并可能最终导致开发出更安全、更有效的痘病毒载体和预防痘病毒感染的新策略。