Interaction of Brucella abortus with the host immune system: Study of two new imm

流产布鲁氏菌与宿主免疫系统的相互作用：两种新免疫系统的研究

• 批准号: 7649299
• 负责人: Fernando Alberto Goldbaum
• 金额: $ 8.1万
• 依托单位: INSTITUTE/RESEARCH/BIOTECHNOLOGY FDN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649299
• 关键词: Active Sites; Acute; Affect; Animals; Applications Grants; Area; B-Lymphocytes; Bacteria; Bacterial Proteins; Biochemical; Biology; Brucella; Brucella abortus; Brucella abortus infection; Brucellosis; Chronic; Chronic Disease; Chronic Phase; Country; Dendritic Cells; Development; Disease; Gram-Negative Bacteria; Health; Homeostasis; Human; Immune; Immune response; Immune system; In Vitro; Infection; Infection Control; Inflammatory Response; Interleukin-10; Light; Longevity; Mammals; Mediating; Minor; Mitogens; Molecular; Mus; Organism; Outcome; Pathogenesis; Phase; Play; Preventive; Receptor Signaling; Research; Role; Signal Transduction; Splenocyte; Therapeutic; Therapeutic Agents; Time; Toll-like receptors; Upper arm; Virulence Factors; Work; Zoonoses; anergy; base; cell type; cellular targeting; comparative; cytokine; in vivo; interest; killings; macrophage; microbial; microorganism; mutant; novel; novel therapeutics; pathogen; public health relevance; receptor

DESCRIPTION (provided by applicant): The study of the interface pathogen-immune system is a relatively new area of intense research. Pathogens with the ability to establish a chronic or persistent infection have evolved sophisticated mechanisms to evade and/or modulate the immune response of their hosts. To this selected group of microorganisms belongs Brucella, a gram-negative, facultative intracellular bacteria that infects a broad range of mammals including humans and is one of the most distributed zoonosis in the world. Brucella abortus, the causative agent of bovine brucellosis, is still a major animal health problem in several countries and inflicts severe economical losses in endemic areas. Additionally, because of its capacity to induce a chronic and debilitating disease in humans and due to the lack of preventive and therapeutic therapies, it is classified as a warfare agent. Brucella, if not properly treated during the initial phases of the disease, establishes a chronic infection and is extremely hard to eliminate. To do so, Brucella has evolved a battery of immune evasion mechanisms that are able to tip the immune response to its own advantage but with minor alterations to the host homeostasis. This fine-tuned modulation is an exquisite example of the evolutionary result of a long-standing interaction between this pathogen and its host. The present application aims at studying two novel immune evasion strategies that we have identified in Brucella abortus. These two mechanisms target two different arms of the immune system: B-lymphocytes of the adaptive immune response and Toll-like receptor signaling in dendritic cells, a central component of the innate immune response. In the first case we propose to further study a polyclonal B-lymphocyte mitogen involved in the splenocyte anergy induced by Brucella during the acute phase of the infection. In the second case, the proposal aims at understanding in detail the function and mode of action of a new group of bacterial proteins with domains homologous to the Tir domains of the Toll-like receptor proteins that are able to interfere and/or modulate the outcome of the innate immune response. The present project will contribute to shed light on certain aspects of the molecular bases underlying the intricate host-pathogen interaction. PUBLIC HEALTH RELEVANCE: The bacterium Brucella causes a serious debilitating disease in animals and humans across the world. Our study will shed light on the mechanisms used by this pathogen to evade the immune response, opening the way for the development of new therapeutic agents.

描述（由申请人提供）：界面病原体-免疫系统的研究是一个相对较新的密集研究领域。具有建立慢性或持续感染能力的病原体已经进化出复杂的机制来逃避和/或调节其宿主的免疫应答。布鲁氏菌属于这组选定的微生物，布鲁氏菌是一种革兰氏阴性兼性细胞内细菌，感染包括人类在内的多种哺乳动物，是世界上分布最广的人畜共患病之一。牛种布氏杆菌（Brucellabortus）是引起牛种布氏杆菌病的病原体，在一些国家仍然是一个主要的动物健康问题，并在流行地区造成严重的经济损失。此外，由于它能够在人类中诱发慢性和使人衰弱的疾病，并且由于缺乏预防和治疗方法，它被归类为战剂。布鲁氏菌如果在疾病的初始阶段没有得到适当的治疗，就会形成慢性感染，并且极难消除。为了做到这一点，布鲁氏菌已经进化出了一系列免疫逃避机制，这些机制能够使免疫反应对自己有利，但对宿主体内平衡有微小的改变。这种微调的调节是这种病原体与其宿主之间长期相互作用的进化结果的一个精致例子。本申请旨在研究我们在流产布鲁氏菌中鉴定的两种新的免疫逃避策略。这两种机制靶向免疫系统的两个不同分支：适应性免疫应答的B淋巴细胞和树突细胞中的Toll样受体信号传导，这是先天免疫应答的中心组成部分。在第一种情况下，我们建议进一步研究多克隆B淋巴细胞有丝分裂原参与布鲁氏菌感染的急性期诱导的脾细胞无能。在第二种情况下，该提案旨在详细了解一组新的细菌蛋白的功能和作用模式，这些细菌蛋白具有与Toll样受体蛋白的Tir结构域同源的结构域，这些结构域能够干扰和/或调节先天免疫应答的结果。本项目将有助于阐明复杂的宿主-病原体相互作用的分子基础的某些方面。公共卫生相关性：布鲁氏杆菌在世界各地的动物和人类中引起严重的衰弱性疾病。我们的研究将揭示这种病原体逃避免疫反应的机制，为开发新的治疗药物开辟道路。