Improved Brucella Vaccine Strains

改进的布鲁氏菌疫苗株

• 批准号: 6532844
• 负责人: THOMAS A FICHT
• 金额: $ 27.65万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532844
• 关键词: Brucellaceae; attenuated microorganism; bacterial vaccines; host organism interaction; laboratory mouse; macrophage; mutant; tissue /cell culture; vaccine development; virulence

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.

描述（由申请人提供）：尽管对布鲁氏菌病的认识更多 两千多年来，人类疾病的识别和治疗 仅在上个世纪有记载。动物疾病的减少是 战略性地用于减少人类疾病。人类感染的治疗 依赖于抗生素治疗，但复发并不罕见， 生物工程的出现，将抗生素耐药性引入 布氏杆菌可能会否定直接治疗人类布氏杆菌病的唯一方法。 人类的布鲁氏菌病可以影响许多不同的组织，但最常见的是 通常与淋巴组织细胞疾病有关， 未经治疗的病毒会侵入其他组织并杀死宿主。疾病取决于 生物体在细胞内存活的能力，包括 在专职吞噬细胞中的持久性。保护性免疫 宿主需要体液和细胞反应，虽然很多 已经在亚单位疫苗的开发上投入了努力， 沿着这些路线取得了一些成功。现有疫苗的安全性 人类使用的菌株是值得怀疑的，因为这些菌株通常用于预防 人工流产，对预防感染的关注较少。的目的 建议的工作是开发基于减毒的改进疫苗， 细胞内存活，以尽量减少生物体的持久性， 刺激保护性免疫反应签名标记的诱变将是 用于在小鼠模型中鉴定毒力减弱的突变体， 细胞内存活的缺陷将在体外在人体中得到验证 巨噬细胞将采用感染的小鼠模型，因为存活率和 该模型中病原体的持续存在依赖于细胞内存活 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研究人类 布鲁氏菌病将评价小鼠中的疫苗接种对两种病毒的保护作用。 腹膜内和口服攻击。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。