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(申请人提供)：致病性耶尔森氏菌的研究。在过去的几十年里，为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了解仍然相对原始。以前的观察表明，特异性的Th1应答对于清除耶尔森菌感染至关重要，但B细胞在宿主防御耶尔森氏菌中的作用尚未得到很好的研究。我们研究的广泛和长期目标是使用各种小鼠模型来详细了解宿主因素，这些宿主因素在调节耶尔森氏菌的耐药性或易感性方面起重要作用，并最终利用这一知识开发针对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反应，确定宿主B细胞在耶尔森氏菌发病中的作用。我们发现，缺乏B细胞的动物表现出对系统注射耶尔森菌的早期抵抗力增强。然而，在最初的低剂量感染中幸存下来的bcr-/-小鼠仅比幼稚的bcr-/-动物对高剂量耶尔森氏菌的再次攻击具有轻微的抵抗力。这些观察表明，B细胞可以抑制耶尔森氏菌的先天免疫反应，但它们也参与了效应性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B细胞在耶尔森氏菌感染过程中调节先天免疫以及初级和记忆性T细胞反应的分子和细胞机制。 为了实现这些目标，将分析B细胞对耶尔森氏菌和耶尔森氏菌分泌产物的细胞因子产生模式，并检查细胞因子如IL-10、IL-6和转化生长因子-β在B细胞介导的对耶尔森菌感染的先天免疫抑制中的作用。此外，还将产生缺乏某些T细胞亚群的BCR-/-小鼠并进行分析，以确定在耶尔森氏菌感染期间，BCR-/-小鼠的T细胞反应是否存在缺陷，以及哪一种T细胞反应存在缺陷。还将产生lgHEL BCR-/-小鼠，这些动物只能产生鸡蛋溶菌酶特异的B细胞。对lgHEL 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细胞是否能够纠正在bcr-/-小鼠中观察到的缺陷T细胞反应，以及是否需要B细胞呈递同源抗原来诱导Th2反应。此外，在初次感染中幸存下来的bcr-/-和lgHEL bcr-/-小鼠将再次接受大剂量耶尔森氏菌的攻击，并将分析T细胞反应，以确定B细胞和抗体是否在维持记忆T细胞方面发挥作用。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保持的，这将导致关于如何最好地设计抗鼠疫疗法的明智决定。