Evaluation of Ail as a protective immunogen for plague

Ail 作为鼠疫保护性免疫原的评价

基本信息

批准号：
8113017
负责人：
ERIC S KRUKONIS
金额：
$ 7.76万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2013-02-28
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：蛋白质的AIL家族已被证明可以介导细胞粘附和对人血清的耐药性，在几种致病性的耶尔森氏菌中。我们最近表明，AIL对于从鼠疫耶尔森氏菌到吞噬细胞和非吞噬细胞细胞的细胞毒性Yop蛋白很重要。在体外分娩中的这种缺陷反映在A（y. pestis kim5的ail突变体通过静脉内感染途径）中的LD50增加> 3,000倍。随着（AIL突变体的毒力降低）（我们还观察到了基于感染的脾脏和liver量的降低的炎症，基于这些细菌和细菌的量减少了这些细菌的炎症，这些炎症增加了这些量的炎症。如果抑制YOP，由于AIL在瘟疫发病机理中的主要作用，导致抗炎酵母无法递送，我们建议使用最近纯化的AIL蛋白来确定AIL免疫的能力来保护天真的小鼠免受野生型（完全毒气）的pest型pecisection（Peste）的下降（PESERAIN）（PESERAIN）（PERINE）用Y. pestis或非免疫抑制衍生物V10的V抗原进行实验性免疫是鼠疫疫苗接种的现场标准，我们还将表征AIL与V10一起提供的合并保护。 Y. Pestis是瘟疫的病因学药，迅速致命的疾病和潜在的生物恐怖威胁。目前，美国尚无许可瘟疫疫苗，最近的报告表明，逃生突变体可能会破坏利用F1胶囊作为免疫原的疫苗的疗效。因此，对未来瘟疫疫苗制剂的额外保护抗原的识别和开发至关重要。鉴于Y.瘟疫剂在Yop递送和毒力中的关键作用，它是使用动物模型进行免疫试验的出色候选抗原。该提案的具体目的是：1。评估AIL免疫对预防鼠疫2中2的功效。评估AIL + V10（V抗原的衍生物）对鼠标累积损害保护的疗效公共卫生相关性：该项目将测试一种新的疫苗抗原AIL的功效，因为它可以保护小鼠免受瘟疫的侵害。如果AIL证明可以保护动物免受疾病的侵害，则可以将其纳入未来的疫苗配方中，以防止人类鼠疫。瘟疫是一种快速致命的传染病和潜在的生物恐怖威胁，目前在美国没有许可疫苗