Improved Brucella Vaccine Strains

描述(由申请人提供)：尽管对布鲁氏菌病有更多的认识 两千多年来，人类疾病的识别和治疗 仅在上个世纪才有记载。动物疾病的减少一直是 在战略上用于减少人类疾病。人类感染的治疗 依赖抗生素治疗，但复发并不少见，随着 生物工程的到来，将抗生素耐药性引入到 布鲁氏菌可能会否定直接治疗人类布鲁氏菌病的唯一方法。 人类中的布鲁氏菌病可以影响许多不同的组织，但最重要的是 通常与淋巴组织细胞性疾病有关，如果留下来 未经治疗会侵入其他组织，并可能杀死宿主。疾病取决于 生物体在细胞内存活的能力，包括 在专业吞噬细胞内的持久性。儿童的保护性免疫 主持人需要体液和细胞反应，尽管有很多 在亚单位疫苗的开发上投入了大量的精力 沿着这些路线，几乎没有什么成功。目前可用的疫苗的安全性 人类使用的菌株是有问题的，因为这些菌株经常被用来防止 堕胎时对预防感染的关注较少。该计划的目的是 建议的工作是开发基于减毒活疫苗的改进疫苗 细胞内存活，以最大限度地减少有机体的持久性 刺激保护性免疫反应。标记签名的突变将是 用于在小鼠模型中识别毒力减弱的突变体 细胞内存活缺陷将在体外人类身上得到验证 巨噬细胞。将采用小鼠感染模型，因为存活和 病原体在这个模型中的持久性依赖于细胞内的存活 在巨噬细胞中。生物体、疾病和器官存活的相似性 参与支持使用小鼠模型来研究人类 布鲁氏菌病。将对小鼠接种疫苗进行评估，以预防这两种疾病 腹膜内和口腔内的挑战。许多已鉴定的基因产物可能 作为新治疗方案的目标，但这超出了 目前的提案。

DESCRIPTION (provided by applicant): Despite awareness of brucellosis for more than two millennia, identification and treatment of human illness is documented only within the last century. Reduction in animal disease has been used strategically to reduce human disease. Treatment of human infection relies upon antibiotic therapies, but relapse is not uncommon and with the advent of bioengineering, the ability to introduce antibiotic resistance into Brucella may negate the only method for direct treatment of human brucellosis. Brucellosis in humans can affect a number of different tissues, but is most typically associated with the lympho-histiocytic disease that if left untreated invades other tissues and can kill the host. Disease depends upon the ability of the organism to survive intracellularly, and includes persistence within professional phagocytic cells. Protective immunity in the host requires both the humoral and cellular responses, and although much effort has been invested in the development of subunit vaccines there has been little of success along these lines. The safety of currently available vaccine strains for human use is questionable, since these are often used to prevent abortion with less concern for protection against infection. The aim of the work proposed is the development of improved vaccines based on attenuated intracellular survival to minimize persistence of the organism while stimulating a protective immune response. Signature-tagged mutagenesis will be used to identify mutants of attenuated virulence in the mouse model and the defect in intracellular survival will be verified in vitro in human macrophages. The mouse model of infection will be employed, since survival and persistence of the pathogen in this model relies upon intracellular survival in macrophages. Similarities in survival of the organism, disease and organ involvement support the use of the mouse model for the study of human brucellosis. Vaccination in mice will be evaluated for protection against both intraperitoneal and oral challenge. Many of the gene products identified may serve as targets for new therapeutic regimens, but that is beyond the scope of the current proposal.