CRYPTOCOCCUS NEOFORMANS--OXIDATIVE KILLING MECHANISMS

描述：（改编自申请人摘要）新型隐球菌 导致艾滋病和血液病患者严重的机会性疾病 恶性肿瘤。 吞噬细胞是抵御这种真菌的第一道防线 而细胞介导的免疫在系统性疾病期间控制真菌。 据信，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患者易于 隐球菌病 然而，目前尚不清楚人体吞噬细胞如何氧化 杀死C。以及真菌如何挫败这种攻击。 此外，初步 观察表明远端嗜中性粒细胞氧化剂是杀真菌的， 真菌甘露醇可以保护免受氧化杀死。 因此中央 本项目所要检验假设是：（1）远距离氧化剂 超氧阴离子（O2-）和过氧化氢（H2 O2）是C. 隐球菌甘露醇作为一种抗肿瘤药物， 抗氧化剂 在具体目标1中，研究者将研究氧化 人单核细胞和中性粒细胞对C.新生 为了鉴定可能包括羟基的杀真菌氧化剂， 次氯酸盐和/或一氧化氮。 具体目标2是确定是否 C.新型甘露醇在白细胞相互作用中作为抗氧化剂发挥作用 采用C.新生儿天然分离株、甘露醇缺失突变体或 过量表达甘露醇 具体目标3是比较甘露醇与 隐球菌黑色素的抗氧化功能。 Mandarin +/-功能 将被引入黑色素+/-菌株中用于氧化剂的比较 测定。 这些研究意义重大，因为它们将i）表征 白细胞氧化剂对C.新形式，ii）定义 C.抗氧化作用新型甘露醇，iii）检查甘露醇的可见光， 黑色素作为抗氧化剂，iv）提示了用于开发 抗真菌药物; iv）为研究吞噬细胞提供方法学基础 氧化剂对其他致病真菌。

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.