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.

鼠疫耶尔森菌是一种高毒性的鼠疫病原体，是一种生物武器。预防鼠疫的策略有 几个世纪以来，人们一直在寻找鼠疫疫苗，但无论是FDA批准的疫苗，还是鼠疫的分子基础， 豁免权已经确立。用减毒活（非色素）Y. 鼠疫菌株提高了保护性免疫力，但相关的副作用禁止使用全细胞 人类的疫苗。以前开发亚单位疫苗的努力结合了两种蛋白抗原，F1和 LcrV，预防淋巴腺鼠疫和肺鼠疫。这个GLRCE资助的研究计划解决了 他还试图了解鼠疫免疫的分子基础。我们的工作 证明Y.鼠疫F1皮利是腺鼠疫或肺鼠疫的致病菌。 在感染过程中，突破性的突变体出现，从此逃脱鼠疫免疫力来自 F1亚单位疫苗或减毒活菌株。在cafIA中携带IS 1541插入的突破突变体 （其指定用于菌毛组装的引导器），表明F1皮利不是合适的疫苗组分。 LcrV亚单位疫苗显示出保护小鼠和非人灵长类动物免受腺病毒和肺炎病毒感染。 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。LcrV位于III型针头的尖端， LcrV保护免疫细胞免受耶尔森氏菌III型效应子Yops的注射，Yops是一种阻断 细菌吞噬作用和宿主免疫细胞的NF-κ B活化。鼠疫菌优先注射 吞噬细胞，并且这种靶选择需要免疫细胞表面上的CD 14和TLR 6。LcrV介导 CD 14/TLR 2/TLR 6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。该更新申请的目标是开发亚单位疫苗 鼠疫保护和评价鼠疫免疫在分子水平上确定的性质， 保护性抗体和Y.鼠疫逃逸变种其他工作将确定TLR 2的贡献， TLR 6和CD 14对Y.鼠疫III型注射剂靶点的选择及其作用机制 由此病原体在鼠疫感染期间逃避免疫力的发展。