Immune modulation mechanism mediated by poxvirus IL-18 binding protein

痘病毒IL-18结合蛋白介导的免疫调节机制

• 批准号: 7690939
• 负责人: YAN XIANG
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690939
• 关键词: Affect; Affinity; Attenuated; Binding; Binding Sites; C-terminal; Cations; Cell Culture Techniques; Cell surface; Cells; Charge; Cowpox; Cytoprotection; Development; Disease; Glycosaminoglycans; Immune response; Immunity; Infection; Inflammatory; Interleukin-18; Lead; Lysine; Mediating; Modeling; Modification; Molecular; Monkeypox virus; Monoclonal Antibodies; Mus; Pathogenesis; Pathogenicity; Population; Positioning Attribute; Poxviridae; Production; Role; Smallpox Vaccine; Smallpox Viruses; Tail; Testing; Therapeutic Intervention; Tyrosine; Vaccines; Vaccinia virus; Virulence; Virus; Virus Diseases; acquired immunity; base; cytokine; immunogenic; immunogenicity; immunoregulation; in vivo; inhibitor/antagonist; interleukin-18 binding protein; interleukin-18 receptor; microbial; mouse model; public health relevance; receptor binding; response; tumor; vector; vector vaccine

DESCRIPTION (provided by applicant): Pathogenic poxviruses such as variola virus and monkeypox virus pose a dangerous threat to today's largely unimmunized population, while attenuated poxviruses hold great promise as vaccine vectors. The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL- 18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. IL-18 is a pleiotropic cytokine that enhances both the innate and acquired immunity [1, 2]. It protects against microbial infection and tumors in murine models. Many poxviruses express an IL-18 binding protein (IL-18BP) that binds to IL-18 with high affinity and inhibits IL-18 mediated immune responses [3-5]. The central hypotheses behind this proposal are that poxvirus IL-18BP greatly affects poxvirus pathogenicity and immunogenicity and that a comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus- based vaccines. Our specific aims are: 1. To further determine the molecular mechanism by which IL-18BP binds and inhibits IL-18. A detailed understanding of the specific interactions between IL-18, IL-18BP and IL-18 receptor at the molecular level will greatly benefit the development of specific inhibitors against IL-18BP and IL-18 for the treatment of infectious and inflammatory diseases. 2. To develop inhibitors against poxvirus IL-18BP and evaluate the effects of these inhibitors at reducing poxvirus pathogenicity. To determine the spatial requirement of poxvirus IL-18BP in poxvirus pathogenesis. 3. To determine the role of IL-18BP in immunogenicity of poxvirus-based vaccine. This will allow a better understanding of the role of IL-18 in the development of protective immune responses and facilitate the development of a safer and more immunogenic vaccine vector. PUBLIC HEALTH RELEVANCE: The need for both anti-poxvirus therapies and better poxvirus-based vaccines demands a deeper understanding of how poxviruses modulate the host immune responses. The focus of this proposal is on a potent interleukin-18 (IL-18) inhibitor that is secreted by a wide variety of poxviruses, including variola virus, monkeypox virus and vaccinia virus. A comprehensive understanding of IL-18BP functioning mechanism and in vivo effects will lead to new therapies for poxvirus diseases and better poxvirus-based vaccines.

描述（由申请人提供）：诸如Variola病毒和Monkeypox病毒之类的致病毒病毒对当今的不受欢迎的人群构成了危险的威胁，而减毒的痘病毒作为疫苗向量具有很大的前景。对抗Poxvirus疗法和更好的基于痘病毒的疫苗的需求需要更深入地了解痘病毒如何调节宿主免疫反应。该提案的重点是由多种多种孢子病毒分泌的有效的白介素-18（IL-18）抑制剂，包括Variola病毒，Monkeypox病毒和Vaccinia病毒。 IL-18是一种多效细胞因子，可增强先天和获得的免疫力[1，2]。它可以预防鼠模型中的微生物感染和肿瘤。许多痘病毒表达IL-18结合蛋白（IL-18bp），该蛋白具有高亲和力与IL-18结合并抑制IL-18介导的免疫反应[3-5]。该提案背后的中心假设是，痘病毒IL-18BP极大地影响了痘病毒的致病性和免疫原性，并且对IL-18BP功能机制的全面了解和体内效应将导致新的癌症疾病疗法，以及基于POXVIRUS-基于Poxvirus-基于poxvirus-的疫苗。我们的具体目的是：1。进一步确定IL-18BP结合并抑制IL-18的分子机制。对分子水平上IL-18，IL-18bp和IL-18受体之间特定相互作用的详细理解将极大地使特定抑制剂针对IL-18BP和IL-18的开发用于治疗感染和炎性疾病。 2。开发针对毒病毒IL-18bp的抑制剂，并评估这些抑制剂对降低痘病毒致病性的影响。确定痘病毒发病机理中痘病毒IL-18bp的空间需求。 3。确定IL-18BP在基于痘病毒的疫苗的免疫原性中的作用。这将使您可以更好地了解IL-18在保护性免疫反应中的作用，并促进更安全，更免疫原性疫苗载体的发展。公共卫生相关性：对抗PoxVirus疗法和更好的基于痘病毒的疫苗的需求都需要对痘病毒如何调节宿主免疫反应有更深入的了解。该提案的重点是由多种多种痘病毒分泌的有效的白介素-18（IL-18）抑制剂，包括Variola病毒，蒙基蛋白病毒和vaccinia病毒。对IL-18BP功能机制和体内效应的全面了解将导致针对痘病毒疾病的新疗法和更好的基于Poxvirus的疫苗。