Immunity to plague infections

对鼠疫感染的免疫力

• 批准号: 8448672
• 负责人: Olaf Schneewind
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448672
• 关键词: Address; Adverse effects; Animals; Antibodies; Antigens; Attenuated; Bacteria; Biological; Bubonic Plague; CD14 gene; Cells; Development; Event; FDA approved; Funding; Generations; Goals; Human; Immune; Immune response; Immunity; Immunization; Infection; Injection of therapeutic agent; Interleukin-10; Intervention; Knockout Mice; Life; Mediating; Molecular; Mus; Natural Immunity; Nature; Needles; Pathogenesis; Phagocytes; Phagocytosis; Pilum; Plague; Plague Vaccine; Pneumonic Plague; Positioning Attribute; Property; Proteins; Research; Research Project Grants; Role; Signal Transduction; Specific qualifier value; Subunit Vaccines; Surface; TLR2 gene; TLR6 gene; Vaccines; Variant; Virulence; Virulent; Whole Cell Vaccine; Work; Yersinia; Yersinia pestis; base; biodefense; cytokine; immunoregulation; in vivo; mutant; nonhuman primate; pathogen; prevent; programs; weapons

Yersinia pestis, the highly virulent agent of plague, is a biological weapon. Strategies to prevent plague have been sought for centuries, however neither an FDA approved vaccine nor the molecular basis of plague immunity are established. Immunization of animals or humans with live-attenuated (non-pigmented) Y. pestis strains raises protective immunity, however associated side effects prohibit the use of whole cell vaccines in humans. Previous efforts to develop subunit vaccines combined two protein antigens, F1 and LcrV, to prevent bubonic and pneumonic plague. This GLRCE funded research program addresses the need for plague vaccines and also seeks to understand the molecular basis of plague immunity. Our work demonstrated that Y. pestis F1 pili are dispensable for the pathogenesis of bubonic or pneumonic plague. During infection, breakthrough mutants emerge that henceforth escape plague immunity derived from either F1 subunit vaccines or live-attenuated strains. Breakthrough mutants carry IS1541 insertions in cafIA (which specifies the usher for pilus assembly), indicating that F1 pili are not a suitable vaccine component. LcrV subunit vaccines were shown to protect mice and non-human primates against bubonic and pneumonic plague. LcrV displays immune modulatory effects. A variant, V10, lacks these properties, but retains the ability to raise protective immunity. LcrV is positioned at the tip of type III needles and antibodies against LcrV protect immune cells from Yersinia type III injection of effector Yops, a virulence mechanism that blocks bacterial phagocytosis and NF-KB activation by host immune cells. Plague bacteria preferentially inject phagocytes and this target selection requires CD14 and TLR6 on the surface of immune cells. LcrVmediated engagement of CD14/TLR2/TLR6 triggers signal transduction cascades, IL-10 release as well as suppression of proinflammatory cytokines. Goals of this renewal application are to develop subunit vaccines for plague protection and to appreciate plague immunity at a molecular level by determining the nature of protective antibodies and Y. pestis escape variants. Other work will determine the contributions of TLR2, TLR6 and CD14 towards Y. pestis selection of targets for type III injection and unravel the mechanisms whereby the pathogen evades the development of immunity during plague infections.

鼠疫的高毒剂耶尔西尼亚·佩斯蒂斯（Yersinia Pestis）是一种生物武器。防止瘟疫的策略 被寻求几个世纪，但是FDA批准的疫苗或鼠疫的分子基础均未 建立了免疫力。具有活体侵蚀（无色素）Y的动物或人类的免疫接种。 病菌株提高保护性免疫，但是相关的副作用禁止使用全细胞 人类的疫苗。以前开发亚基疫苗的努力合并了两种蛋白质抗原F1和 LCRV，以防止泡泡糖和肺炎鼠疫。该GLRCE资助的研究计划解决了 需要瘟疫疫苗，还试图了解鼠疫免疫的分子基础。我们的工作 证明Y. pestis f1 pili对于气泡或肺鼠疫的发病机理是可分配的。 在感染期间，突破突变体出现，此后逃脱了鼠疫免疫。 F1亚基疫苗或活菌株。突破突变体在CAFIA中插入IS1541 （指定菌毛组件的迎接器），表明F1 Pili不是合适的疫苗成分。 显示LCRV亚基疫苗可保护小鼠和非人类灵长类动物免受肺泡和肺炎 瘟疫。 LCRV显示免疫调节作用。一个变体V10缺乏这些属性，但保留了 提高保护性免疫力的能力。 LCRV位于III型针和抗体的尖端 LCRV保护免疫细胞免受Yersinia III型效应YOPS的注射，这是一种阻止的毒力机制 宿主免疫细胞的细菌吞噬作用和NF-KB激活。瘟疫细菌优先注射 吞噬细胞和该目标选择需要在免疫细胞表面上进行CD14和TLR6。 lcrvedied CD14/TLR2/TLR6的参与触发信号转导级联，IL-10释放以及 抑制促炎细胞因子。该更新应用的目标是开发亚基疫苗 通过确定的性质 保护性抗体和Y. Pestis逃生变体。其他工作将决定TLR2的贡献， TLR6和CD14朝向Y. PESTIS选择III型注射靶标的靶标和揭示机制 因此，病原体逃避了鼠疫感染期间免疫的发展。