The Role of Host B Lymphocytes in Yersinia Pathogenesis

宿主 B 淋巴细胞在耶尔森氏菌发病机制中的作用

• 批准号: 7006992
• 负责人: Richard Ian Tapping
• 金额: $ 32.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006992
• 关键词: B cell receptor; B lymphocyte; T lymphocyte; Yersinia; Yersinia pestis; Yersinia pestis disease; antigen presenting cell; bactericidal immunity; cytokine; immunogenetics; immunologic memory; laboratory mouse

DESCRIPTION (provided by applicant): Studies of pathogenic Yersinia spp. over the last several decades have provided important insights into the molecular mechanisms of bacterial virulence. However, our understanding of the immunology of Yersinia infection remains relatively primitive. Previous observations demonstrate that a specific Th1 response is critical for the clearance of Yersinia infection in mice, but the role of B cells in host defense against Yersinia has not been well studied. The broad, long-term objective of our research is to use a variety of mouse models to gain a detailed understanding of host factors that are important in mediating resistance or susceptibility to Yersinia and ultimately to use this knowledge to develop immune therapies for human plague. The focus of this project is to establish a role for host B cells in Yersinia pathogenesis by analyzing immune response to Yersinia infection in wild type, B cell-deficient (BCR-/-}, and RAG-1-/- mice. We found that animals devoid of B cells exhibit enhanced early resistance to systemically administered Yersinia. However, BCR-/- mice that have survived an initial low-dose infection become only slightly more resistant than naive BCR-/- animals to re-challenge by a high dose of Yersinia. These observations suggest that B cells can inhibit innate immune response to Yersinia but they are also involved in either the generation of effector T cells, or the maintenance of memory T cells, or both. Our goals are to elucidate the molecular and cellular mechanisms by which B cells modulate both innate immunity and primary and memory T-cell response during Yersinia infection. To achieve these goals, the pattern of cytokine production by B cells in response to Yersinia and Yersinia -secreted products will be analyzed, and the role of cytokines such as IL-10, lL-6, and TGF-beta in B cell-mediated inhibition of innate immunity to Yersinia infection will be examined. In addition, BCR-/- mice that lack certain subset of T cells will be generated and analyzed to determine whether BCR-/- mice are defective in T-cell response during Yersinia infection and which subset of T-cell response is defective. lgHEL BCR-/- mice will also be generated, and these animals can produce only hen egg lysozyme-specific B cells. Analysis of Yersinia infection in lgHEL BCR-/- mice will determine whether Yersinia -nonspecific B cells can correct the defective T-cell response observed in BCR-/- mice and whether cognate antigen presentation by B cells is required for the induction of a Th2 response. Furthermore, BCR-/- and lgHEL BCR-/- mice that have survived a primary infection will be re-challenged with a high dose of Yersinia and T-cell response will be analyzed to determine whether B cells and antibodies play a role in the maintenance of memory T cells. A detailed understanding of how Yersinia infection is cleared and how immunological memory is maintained will lead to informed decision on how best to design an anti-plague therapy.

描述（由申请方提供）：致病性耶尔森氏菌属的研究。在过去几十年中，对细菌毒力的分子机制提供了重要的见解。然而，我们对耶尔森氏菌感染的免疫学的理解仍然相对原始。以前的观察表明，一个特定的Th 1反应是至关重要的清除耶尔森氏菌感染的小鼠，但B细胞在宿主防御耶尔森氏菌的作用还没有得到很好的研究。我们研究的广泛，长期目标是使用各种小鼠模型来详细了解介导耶尔森氏菌抗性或易感性的宿主因素，并最终利用这些知识开发人类鼠疫的免疫疗法。本项目的重点是通过分析野生型、B细胞缺陷（BCR-/-）和RAG-1-/-小鼠对耶尔森氏菌感染的免疫应答，确定宿主B细胞在耶尔森氏菌发病机制中的作用。我们发现，缺乏B细胞的动物表现出增强的早期抵抗系统管理耶尔森氏菌。然而，在最初的低剂量感染中存活的BCR-/-小鼠对高剂量耶尔森氏菌再攻击的抵抗力仅略高于幼稚BCR-/-动物。这些观察结果表明，B细胞可以抑制对耶尔森氏菌的先天性免疫应答，但它们也参与效应T细胞的产生或记忆T细胞的维持，或两者兼而有之。我们的目标是阐明在耶尔森氏菌感染过程中，B细胞调节先天性免疫和原发性及记忆性T细胞应答的分子和细胞机制。 为了实现这些目标，将分析B细胞响应耶尔森氏菌和耶尔森氏菌分泌产物产生细胞因子的模式，并将检查细胞因子如IL-10、IL-6和TGF-β在B细胞介导的对耶尔森氏菌感染的先天免疫的抑制中的作用。此外，将产生并分析缺乏某些T细胞亚群的BCR-/-小鼠，以确定BCR-/-小鼠在耶尔森氏菌感染期间是否存在T细胞应答缺陷，以及哪种T细胞应答亚群存在缺陷。还将产生IgHEL BCR-/-小鼠，并且这些动物只能产生鸡蛋溶菌酶特异性B细胞。IgHEL BCR-/-小鼠中耶尔森氏菌感染的分析将确定耶尔森氏菌非特异性B细胞是否可以纠正在BCR-/-小鼠中观察到的缺陷性T细胞应答，以及诱导Th 2应答是否需要B细胞的同源抗原呈递。此外，将用高剂量耶尔森氏菌再次攻击在初次感染后存活的BCR-/-和IgHEL BCR-/-小鼠，并分析T细胞应答以确定B细胞和抗体是否在记忆T细胞的维持中发挥作用。详细了解耶尔森氏菌感染是如何清除的，以及免疫记忆是如何维持的，将有助于我们做出明智的决定，如何最好地设计一种抗鼠疫疗法。