IMMUNOREACTIVE MACROMOLECULES OF COCCIDIOIDES CELL TYPES

描述（由申请人提供）：球孢子菌病是一种真菌性呼吸道疾病，是美国西南部沙漠地区的地方病。最常见的临床表现是自限性肺炎，尽管该真菌也能够在免疫功能正常的个体中建立全身感染。宿主抵抗球孢子虫感染的关键是T细胞介导的免疫。T细胞的辅助性T细胞1（Th 1）亚群分泌激活巨噬细胞的细胞因子，巨噬细胞有助于保护，而Th 2细胞分泌刺激B细胞产生抗体的细胞因子，抗体似乎对真菌病几乎没有保护作用。对粗球孢子菌感染的抗性/易感性与小鼠中引起的细胞因子应答谱之间存在相关性。研究表明，与对照组相比，在腹腔内激发之前或之后向易感BALB/c小鼠给予白细胞介素（IL-12）可促进干扰素（IFN-γ）的产生，并显著降低这些动物的真菌负荷。也有证据表明，IL-10表达的上调，抑制刺激Th 1途径的免疫反应，可以加剧某些品系的近交系小鼠对球虫感染的易感性。我们的中心假设是C.犬肠炎是多种基因体内表达的结果，其产物有助于宿主组织的定殖、调节宿主免疫应答以利于病原体、以及维持可导致宿主组织损伤的持续性炎症应答。该项目的主要目标是对C.在先天免疫细胞的刺激和激活Th 1或Th 2免疫应答的特异性细胞因子和趋化因子的产生后，免疫性炎症可被抑制。该项目的具体目标是集中研究四个C。immitis基因产物，其中三个似乎有助于感染的起始和转移，一个刺激宿主保护免受球虫感染。我们已经概述了一个多方面的方法来评估这四种基因产物对疾病发展过程的影响。我们认为，这些研究的结果将显着推进我们对C的发病机制的理解。免疫球蛋白

DESCRIPTION (provided by applicant): Coccidioidomycosis is a fungal respiratory disease which is endemic to desert regions of the Southwestern U.S. The most common clinical presentation is self-limited pneumonia, although the fungus is also capable of establishing systemic infections in immunocompetent individuals. The pivotal arm of host defense against coccidioidal infection is T cell mediated immunity. The T helper 1 (Th1) subset of T cells secretes cytokines that activate macrophages which contribute to protection, while Th2 cells secrete cytokines that stimulate B cells to produce antibodies which seem to provide little protection against the mycosis. A correlation exists between resistance/susceptibility to Coccidioides immitis infection and the profile of cytokine response elicited in mice. It has been shown that administration of interleukin (IL-12) to susceptible BALB/c mice either before or after intraperitoneal challenge promoted the production of interferon (IFN-gamma) and significantly reduced the fungal burden in these animals compared to controls. Evidence has also been presented that upregulation of IL-10 expression, which inhibits stimulation of the Th1 pathway of immune response, can exacerbate susceptibility to coccidioidal infection in certain strains of inbred mice. Our central hypothesis is that the virulence phenotype of C. immitis is the result of in vivo expression of multiple genes, the products of which contribute to colonization of host tissue, modulation of host immune response to the advantage of the pathogen, and maintenance of a persistent inflammatory response which can result in host tissue damage. The major goal of the proposed project is to develop a fundamental understanding of the influence of selected antigens of C. immitis upon the stimulation of innate immune cells and production of specific cytokines and chemokines that activate either a Th1 or Th2 immune response. The specific aims of the project are focused on studies of four C. immitis gene products, three of which appear to contribute to the initiation and metastasis of the infection, and one which stimulates host protection against coccidioidal infection. We have outlined a multifaceted approach to the evaluation of the impact of these four gene products on the course of disease development. We suggest that the results of these studies will significantly advance our understanding of the pathogenesis of C. immitis.