Development of an improved vaccine against Brucella abortus

项目概要 布鲁氏菌属是自然感染各种家养和野生动物的细菌，导致 流产和不育，这些细菌还能够引起使人衰弱的人类感染，这 通常是由于人类接触受感染的动物和动物产品所致。布鲁氏菌属被认为 作为潜在生物武器的威胁。重要的是，针对布鲁氏菌病的抗生素治疗很容易患病 复发，目前还没有安全有效的疫苗可以保护人类免受布鲁氏菌感染。 布鲁氏菌是细胞内病原体，驻留在称为巨噬细胞的免疫细胞内 在专门的隔室中复制，以及布鲁氏菌在其中生存和复制的能力 巨噬细胞对于其引起疾病的能力至关重要。近几年来，我们实验室 确定了对布鲁氏菌的细胞内存活和发病机制至关重要的遗传途径 菌株，特别是，我们已经鉴定出对布鲁氏菌至关重要的小调节 RNA (sRNA) 毒力。 初步实验表明，sRNA 家族（称为 AbcR）是 流产布鲁氏菌长期感染小鼠的能力。当这些基因编码这两个 sRNA（即 AbcR1 和 AbcR2）被删除，所得菌株高度减毒，而且，我们已经确定该菌株 缺失菌株产生极高水平的布鲁氏菌免疫原性蛋白。我们假设 abcR1 abcR2 缺失菌株可作为针对流产布鲁氏菌的高效活减毒疫苗 挑战，本申请中概述的试点研究将检验这一假设。最后，信息 从这些研究中收集到的信息可用于开发针对人类布鲁氏菌感染的有效疫苗。

Project Summary Brucella spp. are bacteria that naturally infect a variety of domesticated and wild animals leading to abortions and sterility, and these bacteria are also capable of causing debilitating human infections, which often result from human exposure to infected animals and animal products. Brucella spp. are considered threats as potential biological weapons. Importantly, antibiotic treatment against brucellosis is prone to disease relapse, and there is currently no safe and effective vaccine to protect humans against infection with Brucella. The brucellae are intracellular pathogens that reside within immune cells called macrophages where they replicate in a specialized compartment, and the capacity of Brucella to survive and replicate within macrophages is essential to their ability to cause disease. Over the last few years, our laboratory has characterized genetic pathways that are critical for the intracellular survival and pathogenesis of Brucella strains, and specifically, we have identified small regulatory RNAs (sRNAs) that are essential for Brucella virulence. Preliminary experiments have demonstrated that a family of sRNAs, called the AbcRs is required for the ability of B. abortus to chronically infect mice. When these genes encoding these two sRNAs (i.e., AbcR1 and AbcR2) are deleted, the resulting strain is highly attenuated, and moreover, we have determined that this deletion strain produces extremely high levels of Brucella immunogenic proteins. We hypothesize that the abcR1 abcR2 deletion strain can serve as a highly effective live, attenuation vaccine against B. abortus challenge, and the pilot studies outlined in this application will test this hypothesis. In the end, the information gleaned from these studies may be used to develop an effective vaccine against human Brucella infection.