Evaluation of Ail as a protective immunogen for plague

描述（由申请人提供）：已经证明，在几种致病性耶尔森菌中，Ail家族蛋白介导细胞粘附和对人血清的抗性。我们最近发现，在鼠疫耶尔森菌向吞噬细胞和非吞噬细胞递送细胞毒性Yop蛋白的过程中，Ail起着重要作用。体外传递Yop的这一缺陷反映在鼠疫杆菌KIM5突变体的LD50通过静脉感染途径增加了约3000倍。随着（ail）突变体的毒力下降，我们还观察到感染的脾脏和肝脏组织的组织学炎症增加，感染三天后这些组织中的细菌负荷大大减少。如果Yop的分泌受到抑制，导致抗炎Yops的分泌不足，这是预期的结果。由于Ail在鼠疫发病机制中的重要作用，我们建议使用最近纯化的Ail蛋白来确定Ail免疫保护幼稚小鼠免受野生型（完全毒力）鼠疫菌皮下（腺鼠疫）或鼻内（肺鼠疫）感染的能力。鉴于鼠疫杆菌V抗原或非免疫抑制衍生物V10的实验性免疫是鼠疫疫苗接种领域的标准，我们还将描述Ail与V10的联合保护作用。鼠疫杆菌是鼠疫的病原，鼠疫是一种迅速致命的疾病，具有潜在的生物恐怖威胁。目前在美国还没有获得许可的鼠疫疫苗，最近的报告表明，逃逸突变体可能会破坏使用F1胶囊作为免疫原的疫苗的功效。因此，鉴定和开发用于未来鼠疫疫苗配方的其他保护性抗原至关重要。鉴于鼠疫杆菌在Yop传递和毒力中的关键作用，它是使用动物模型进行免疫试验的优秀候选抗原。本建议的具体目的是：1。评价all免疫预防小鼠鼠疫的效果评估Ail + V10 （V抗原的衍生物）对小鼠的累积鼠疫防护效果

DESCRIPTION (provided by applicant): The Ail family of proteins has been shown to mediate cell adhesion and resistance to human serum in several pathogenic Yersinia species. We have recently shown that Ail is important for delivery of cytotoxic Yop proteins from Yersinia pestis to phagocytic and non-phagocytic human cells. This defect in Yop delivery in vitro is reflected in the >3,000-fold increase in LD50 of a (ail mutant of Y. pestis KIM5 by the intravenous route of infection. Along with the decreased virulence of the (ail mutant, we also observed increased inflammation within infected spleen and liver tissues based on histology and greatly decreased bacterial loads in these tissues three days post- infection. This is the expected result if Yop delivery is inhibited, leading to lack of delivery of anti-inflammatory Yops. Due to the major role of Ail in plague pathogenesis, we propose to use a recently purified Ail protein to determine the ability of Ail immunization to protect naive mice from wild-type (fully virulent) Y. pestis infection delivered subcutaneously (bubonic plague) or intranasally (pneumonic plague). Given that experimental immunization with V antigen of Y. pestis or the non-immunosuppressive derivative V10 are standards in the field for plague vaccination, we will also characterize the combined protection provided by Ail together with V10. Y. pestis is the etiological agent of plague, a rapidly fatal disease and potential bioterrorism threat. There is currently no licensed plague vaccine in the U.S. and recent reports indicate escape mutants may undermine the efficacy of vaccines utilizing the F1 capsule as an immunogen. Thus, identification and development of additional protective antigens for future plague vaccine formulations are essential. Given the critical role for Y. pestis Ail in Yop delivery and virulence, it is an excellent candidate antigen for immunization trials using an animal model. The specific Aims of this proposal are: 1. Assess the efficacy of Ail immunization for preventing plague in mice 2. Assess the efficacy of Ail + V10 (a derivative of V antigen) for cumulative plague protection in mice PUBLIC HEALTH RELEVANCE: This project will test the efficacy of a new vaccine antigen, Ail, for its ability to protect mice from plague. If Ail proves to protect animals from disease, it could be incorporated into future vaccine formulations to prevent plague in humans. Plague is a rapidly-fatal infectious disease and potential bioterrorism threat with no currently licensed vaccine in the U.S.