CRYPTOCOCCUS NEOFORMANS--OXIDATIVE KILLING MECHANISMS

新型隐球菌——氧化杀伤机制

• 批准号: 6170938
• 负责人: VISHNU CHATURVEDI
• 金额: $ 11.19万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170938
• 关键词: Cryptococcus neoformans; antioxidants; electron spin resonance spectroscopy; gene mutation; genetic strain; host organism interaction; human tissue; laboratory mouse; mannitol; melanins; microorganism immunology; molecular cloning; monocyte; neutrophil; oxidation

DESCRIPTION: (Adapted from Applicant's Abstract) Cryptococcus neoformans causes serious opportunistic disease in patients with AIDS and hematologic malignancies. Phagocytes provide first line of defense against this fungus whereas cell-mediated immunity controls the fungus during systemic disease. It is believed that general defects in monocyte and neutrophil functions combined with impaired T cell responses predispose HIV patients to cryptococcosis. However, it is not know how human phagocytes oxidatively kill C. neoformans and how the fungus foils such attacks. Also, preliminary observations suggest that a distal neutrophil oxidant is fungicidal and that fungal mannitol may protect from oxidative killing. Therefore, the central hypotheses to be tested in this project are: (1) that oxidants distal to superoxide anion (O2-) and hydrogen peroxide (H2O2) are critical in C. neoformans killing and (2) that cryptococcal mannitol acts as an antioxidant. In Specific Aim 1, the investigator will study oxidative killing mechanisms of human monocytes and neutrophils against C. neoformans to identify fungicidal oxidants that may include hydroxyl radicals, hypochlorite, and/or nitric oxide. Specific Aim 2 is to determine whether C. neoformans mannitol functions as an antioxidant in leukocyte interactions by employing C. neoformans natural isolates, mutants deleted in mannitol or over-expressing mannitol. Specific Aim 3 is to compare mannitol with cryptococcal melanin for their antioxidant functions. Mannitol +/- features will be introduced into melanin +/- strains for comparison in oxidant assays. These studies are significant because they will i) characterize leukocyte oxidants that are fungicidal for C. neoformans, ii) define the antioxidant role of C. neoformans mannitol, iii) examine mannitol vis a vis melanin as an antioxidant, iv) suggest unique targets for developing antifungals, and iv) provide methodological basis to study phagocyte oxidants against other pathogenic fungi.

描述：（改编自申请人的摘要）neoformans 引起艾滋病患者和血液学患者的严重机会性疾病 恶性肿瘤。 吞噬细胞提供对这种真菌的第一道防线 而细胞介导的免疫控制在全身性疾病期间控制真菌。 据认为，单核细胞和中性粒细胞功能的一般缺陷 结合受损的T细胞反应使HIV患者倾向于 隐球菌病。 但是，不知道人类的吞噬细胞如何氧化 杀死C. Neoformans，以及真菌如何挫败此类攻击。 另外，初步 观察结果表明，中性粒细胞氧化剂是杀真菌剂，并且 真菌甘露醇可能可以防止氧化杀死。 因此，中央 在此项目中要测试的假设是：（1） 超氧化物阴离子（O2-）和过氧化氢（H2O2）在C中至关重要。 Neoformans杀人和（2）加密摄像头甘露醇充当 抗氧化剂。 在特定的目标1中，研究者将研究氧化剂 人类单核细胞和嗜中性粒细胞对新近甲状腺癌的杀戮机制 确定可能包括羟基自由基的杀真菌氧化剂， 次氯酸盐和/或一氧化氮。 具体目标2是确定是否 C. Neoformans甘露醇作为白细胞相互作用的抗氧化剂 通过采用新生菌天然分离株，在甘露醇中删除的突变体或 过表达的甘露醇。 特定目的3是将甘露醇与 用于抗氧化剂功能的加密局局部黑色素。 甘露醇+/-特征 将引入黑色素+/-菌株以进行比较 测定。 这些研究很重要，因为它们会）表征 杀真菌的白细胞氧化剂，用于新生梭菌，ii）定义 新近甲醇的抗氧化作用，iii）检查甘露醇 黑色素作为抗氧化剂，iv）提出了开发的独特目标 抗真菌剂，iv）提供了研究吞噬细胞的方法论基础 针对其他致病真菌的氧化剂。