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: 7508569
• 负责人: YAN XIANG
• 金额: $ 33.3万
• 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/7508569
• 关键词: Affect; Affinity; Attenuated; Binding; Binding Sites; C-terminal; Cations; Cell surface; Cells; Charge; Cowpox; Cultured Cells; Cytoprotection; Depth; 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; Public Health; Role; Smallpox Vaccine; Smallpox Viruses; Tail; Testing; Therapeutic Intervention; Today; Tyrosine; United States Food and Drug Administration; 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; 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）：致病性痘病毒，如天花病毒和猴痘病毒，对当今大部分未免疫人群构成危险威胁，而减毒痘病毒作为疫苗载体具有很大的前景。对抗痘病毒疗法和更好的痘病毒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。该提案的重点是一种有效的白细胞介素-18（IL- 18）抑制剂，该抑制剂由多种痘病毒分泌，包括天花病毒、猴痘病毒和牛痘病毒。IL-18是一种多效性细胞因子，可增强先天性和获得性免疫[1，2]。它在小鼠模型中保护免受微生物感染和肿瘤。许多痘病毒表达IL-18结合蛋白（IL-18 BP），其以高亲和力结合IL-18并抑制IL-18介导的免疫应答[3-5]。该提议背后的中心假设是痘病毒IL-18 BP极大地影响痘病毒致病性和免疫原性，并且全面理解IL-18 BP功能机制和体内作用将导致痘病毒疾病的新疗法和更好的基于痘病毒的疫苗。我们的具体目标是：1.进一步确定IL-18 BP结合和抑制IL-18的分子机制。在分子水平上深入了解IL-18、IL-18 BP和IL-18受体之间的特异性相互作用，将有助于开发针对IL-18 BP和IL-18的特异性抑制剂，用于治疗感染性和炎症性疾病。2.目的：开发抗痘病毒IL-18 BP的抑制剂，并评价这些抑制剂降低痘病毒致病性的效果。确定痘病毒IL-18 BP在痘病毒发病机制中的空间需求。3.探讨IL-18 BP在痘病毒疫苗免疫原性中的作用。这将允许更好地理解IL-18在保护性免疫应答的发展中的作用，并促进更安全和更具免疫原性的疫苗载体的开发。公共卫生相关性：对抗痘病毒疗法和更好的痘病毒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。该提案的重点是一种有效的白细胞介素-18（IL-18）抑制剂，该抑制剂由多种痘病毒分泌，包括天花病毒、猴痘病毒和牛痘病毒。全面了解IL-18 BP的作用机制和体内效应，将为痘病毒疾病的治疗和更好的痘病毒疫苗提供新的思路。