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: 7173346
• 负责人: Richard Ian Tapping
• 金额: $ 31.64万
• 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/7173346
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacteria; Bioterrorism; CD8B1 gene; Complex; Defect; Disease; Dose; Exhibits; Ferns; Gene Expression; Generations; Goals; Heating; Hen Egg Lysozyme; Host Defense; Human; Immune response; Immunity; Immunoglobulins; Immunologic Memory; Immunology; Immunosuppression; Immunotherapy; Infection; Integration Host Factors; Interleukin-10; Knowledge; Lead; Life; Maintenance; Mediating; Molecular; Mus; Mutant Strains Mice; Natural Immunity; Organism; Pasteurella pseudotuberculosis; Pathogenesis; Pattern; Personal Satisfaction; Plague; Play; Predisposition; Production; Research; Research Personnel; Resistance; Role; Secondary to; Study models; T memory cell; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; TAP1 gene; Therapeutic immunosuppression; Transforming Growth Factor beta; Virulence; Yersinia; Yersinia enterocolitica; Yersinia infections; Yersinia pestis; Yersinia pestis V antigen; cytokine; design; insight; interest; killings; mouse model; pathogen; programs; response

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（由申请人提供）：致病性耶尔森氏菌的研究。在过去的几十年里，人们对细菌毒力的分子机制提供了重要的见解。然而，我们对耶尔森菌感染免疫学的理解仍然相对原始。先前的观察表明，特定的 Th1 反应对于清除小鼠耶尔森氏菌感染至关重要，但 B 细胞在宿主防御耶尔森氏菌中的作用尚未得到充分研究。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对于介导耶尔森氏菌耐药性或易感性很重要的宿主因素，并最终利用这些知识开发针对人类鼠疫的免疫疗法。该项目的重点是通过分析野生型 B 细胞缺陷型 (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机制中的作用。我们发现，缺乏 B 细胞的动物对全身注射耶尔森氏菌表现出增强的早期抵抗力。然而，在最初的低剂量感染中幸存下来的 BCR-/- 小鼠的抵抗力仅略有增强 比幼稚的 BCR-/- 动物更容易受到高剂量耶尔森氏菌的重新攻击。这些观察结果表明，B 细胞可以抑制针对耶尔森氏菌的先天免疫反应，但它们也参与效应 T 细胞的生成或记忆 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期间调节先天免疫以及初级和记忆 T 细胞反应的分子和细胞机制 感染。 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，并检查细胞因子（如 IL-10、IL-6 和 TGF-β）在 B 细胞介导的耶尔森氏菌感染先天免疫抑制中的作用。此外，将生成并分析缺乏某些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细胞反应缺陷以及哪一个T细胞反应亚群存在缺陷。 lgHEL BCR-/-小鼠也将被产生，并且这些动物只能产生鸡蛋溶菌酶特异性的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 细胞是否可以纠正 BCR-/- 小鼠中观察到的有缺陷的 T 细胞反应，以及诱导 Th2 反应是否需要 B 细胞呈递同源抗原。此外，在初次感染中幸存下来的 BCR-/- 和 lgHEL BCR-/- 小鼠将再次受到高剂量耶尔森氏菌的攻击，并且将分析 T 细胞反应，以确定 B 细胞和抗体是否在维持记忆 T 细胞中发挥作用。详细了解如何清除耶尔森氏菌感染以及如何维持免疫记忆将有助于就如何最好地设计抗鼠疫疗法做出明智的决定。