The Role of Host B Lymphocytes in Yersinia Pathogenesis

描述（由申请人提供）：在过去的几十年里，对致病性耶尔森氏菌的研究为细菌毒力的分子机制提供了重要的见解。然而，我们对耶尔森菌感染的免疫学理解仍然相对原始。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在介导对耶尔森菌的抗性或易感性中起重要作用的宿主因素，并最终利用这些知识开发针对人类鼠疫的免疫疗法。本项目的重点是通过分析野生型、B细胞缺陷型（BCR-/-}）和RAG-1-/-小鼠对耶尔森菌感染的免疫反应，确定宿主B细胞在耶尔森菌发病机制中的作用。我们发现缺乏B细胞的动物对系统给药的耶尔森菌表现出增强的早期耐药性。然而，在最初低剂量感染中存活下来的BCR-/-小鼠对高剂量耶尔森菌再次攻击的抵抗力仅略高于初始BCR-/-小鼠。这些观察结果表明，B细胞可以抑制对耶尔森菌的先天免疫反应，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B细胞在感染耶尔森菌时调节先天免疫和原代和记忆t细胞反应的分子和细胞机制。

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.