Immunity to plague infections

鼠疫耶尔森氏菌是一种生物武器，是鼠疫的高致死性病原体。预防鼠疫的策略有 几个世纪以来一直在寻找，然而既没有FDA批准的疫苗，也没有鼠疫的分子基础 已经确立了豁免权。用活的减毒(非色素)Y型疫苗免疫动物或人。 鼠疫菌株提高了保护性免疫力，然而相关的副作用禁止使用全细胞 人体内的疫苗。以前开发亚单位疫苗的努力结合了两种蛋白质抗原，F1和 LCRV，预防腺鼠疫和肺鼠疫。这个由GLRCE资助的研究项目致力于 我们需要鼠疫疫苗，并试图了解鼠疫免疫的分子基础。我们的工作 证明鼠疫F1菌毛在腺鼠疫或肺鼠疫的发病机制中是必不可少的。 在感染期间，突破性突变体出现，从此以后逃避鼠疫免疫 F1亚单位疫苗或减毒活毒株。突破性突变体在afia中携带IS1541插入 (指定菌毛组装的引座者)，表明F1菌毛不是合适的疫苗成分。 研究表明，LcrV亚单位疫苗可以保护小鼠和非人类灵长类动物免受肺炎性肺炎和肺炎性肺炎的侵袭。 瘟疫。LCRV具有免疫调节作用。变种V10缺少这些属性，但保留了 提高保护性免疫力的能力。LcrV位于III型针的顶端，抗体针对 LcrV保护免疫细胞免受III型耶尔森氏菌注射效应器YOPs的影响，YOPs是一种阻止 宿主免疫细胞的细菌吞噬和核因子-kB活化。鼠疫细菌优先注射 这种靶点选择需要免疫细胞表面的CD14和TLR6。LcrV中介 CD14/TLR2/TLR6参与触发信号转导通路、IL-10释放以及 抑制促炎细胞因子。这项更新申请的目标是开发亚单位疫苗 通过确定鼠疫的性质，在分子水平上评价鼠疫免疫 保护性抗体和鼠疫耶尔森氏菌逃逸变体。其他工作将确定TLR2的贡献， TLR6和CD14对鼠疫杆菌III型注射靶点的选择及其作用机制的研究 在鼠疫感染期间，病原体逃避免疫力的发展。

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.