Host control in Coccidioidomycosis

球孢子菌病的宿主控制

• 批准号: 6904461
• 负责人: JOHN N GALGIANI
• 金额: $ 81.07万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6904461
• 关键词: bioterrorism /chemical warfare; clinical research; coccidioidomycosis; host organism interaction; human subject; human tissue

DESCRIPTION (provided by applicant): Coccidioidomycosis is a national public health problem with special intensity to Arizona, for patients with AIDS or other immunosuppression, women during pregnancy, and some ethnic minorities. It poses problems for the military and Coccidioides spp. are a potential threat to homeland security. Current therapies are inadequate. The University of Arizona has the only medical school situated within the endemic region, can support research in the biological sciences, and has an ongoing commitment improve our control of coccidioidomycosis. The unifying approach of this MRU proposal is to identify and validate Coccidioides target antigens while studying the adaptive responses of both the infecting organism and the infected host. Project 1 will improve our ability to evaluate vaccine candidates for possible clinical trials. Current assessments are highly dependent upon experimental conditions, making their interpretation ambiguous. Project 1 will use immunohistochemistry, proteomic analyses, and in situ hybridization to determine the histologic patterns of genetic and acquired resistance. We shall also examine similarities between the histological response in humans and mice. Project 2 will focus on how the fungus itself participates in the host's recovery from illness. We hypothesize that a quiescent spherule state is produced by specialized gene expression analogous to the quiescence after conidiation or other dormant saprobic structures. Gene expression will be determined from analysis of long-SAGE libraries of in vitro grown Coccidioides spp. with extension to in vivo studies of susceptible and resistant mice. Selected fungal genes associated with quiescence by these methods will be disrupted using Agrobacterioum tumefaciens-mediated transformation. Gene expression responsible for quiescence could identify novel targets for therapeutic benefit. Project 3 intends to develop an immunologic therapy for patients with widely disseminated coccidioidomycosis. Antigen-specific anergy in coccidioidomycosis can be reversed in vitro with dendritic cells (DC). To translate this advance to practical therapy, similar effects will need to be elicited by defined recombinant antigens. This project will evaluate conditions using DC as a vehicle to deliver recombinant antigens with adjuvants such as CpGs and MPL. We will also analyze the phenotype, function and cytokine profiles of lymphocyte subsets that respond to antigen-pulsed DC.

描述（由申请人提供）：球孢子菌病是亚利桑那州的一个全国性公共卫生问题，对于艾滋病或其他免疫抑制患者、怀孕期间的妇女和一些少数民族来说尤为严重。它给军队和球孢子菌带来了问题。是对国土安全的潜在威胁。目前的治疗方法还不够充分。亚利桑那大学拥有位于流行地区的唯一一所医学院，可以支持生物科学研究，并持续致力于改善我们对球孢子菌病的控制。该 MRU 提案的统一方法是识别和验证球孢子菌目标抗原，同时研究感染生物体和受感染宿主的适应性反应。项目 1 将提高我们评估候选疫苗以进行可能的临床试验的能力。目前的评估高度依赖于实验条件，这使得它们的解释含糊不清。项目 1 将使用免疫组织化学、蛋白质组分析和原位杂交来确定遗传性和获得性耐药性的组织学模式。我们还将研究人类和小鼠组织学反应之间的相似性。项目 2 将重点关注真菌本身如何参与宿主的疾病康复。我们假设静止小球状态是由专门的基因表达产生的，类似于分生孢子或其他休眠腐生结构后的静止。基因表达将通过对体外生长的球孢子菌属的长 SAGE 文库的分析来确定。并扩展到易感和耐药小鼠的体内研究。通过这些方法选择的与静止相关的真菌基因将使用根癌农杆菌介导的转化来破坏。负责静止的基因表达可以识别具有治疗益处的新靶点。项目 3 旨在为广泛传播的球孢子菌病患者开发一种免疫疗法。球孢子菌病中的抗原特异性无反应性可以在体外用树突状细胞 (DC) 逆转。为了将这一进展转化为实际治疗，需要通过确定的重组抗原来引发类似的效果。该项目将评估使用 DC 作为载体传递重组抗原以及 CpG 和 MPL 等佐剂的条件。我们还将分析对抗原脉冲 DC 做出反应的淋巴细胞亚群的表型、功能和细胞因子谱。