CRYPTOCOCCUS NEOFORMANS--OXIDATIVE KILLING MECHANISMS

新型隐球菌——氧化杀伤机制

• 批准号: 2673128
• 负责人: VISHNU CHATURVEDI
• 金额: $ 10.57万
• 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/2673128
• 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：（改编自申请人摘要）新生隐球菌