MECHANISMS OF ALCOHOL PATHOGENESIS IN RESPONSE TO HYPOXIA IN A FUMIGATUS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 烟曲霉菌是一种腐生性丝状真菌，是免疫功能低下患者侵袭性机会性霉菌感染的最常见病原体。我们目前还不了解烟曲霉菌在免疫功能低下的宿主中存活和致病的机制。在哺乳动物的发病过程中，所有的病原微生物都暴露在快速变化的氧气水平中。氧是有氧呼吸中关键的电子受体，生物体必须具有替代机制来处理体内感染部位的低氧(低氧)条件。我们的假设是，烟曲霉利用酒精发酵途径存活在肺部侵袭性曲霉病体内发现的炎症反应中。这一假说建立在对感染烟曲霉菌的小鼠支气管肺泡灌洗液的代谢组学研究的初步数据基础上，这些数据表明在真菌感染期间体内会产生乙醇。我们正在探索酒精发酵途径是否对烟曲霉菌致病重要，方法是通过利用酒精发酵途径创造对低氧条件反应能力不足的烟曲霉菌基因突变株。我们目前已经在烟曲霉菌中鉴定了与酒精发酵相关的基因，并产生了缺失这些基因的突变体。在过去的一年里，我们检测了这些酒精缺乏菌株对真菌的毒力，发现酒精发酵的丧失并不影响烟曲霉菌的毒力。低氧条件下电子传递的其他机制可能是这一结果的解释，目前正在探索中。通过直接控制真菌感染部位的氧气水平，这一建议的结果具有潜在的临床意义，并有可能产生当前抗真菌药物的更高疗效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aspergillus fumigatus is a saprophytic filamentous fungus that is the most frequent causative agent of invasive opportunistic mould infections in immunocompromised patients. We currently do not understand the mechanisms used by A. fumigatus to survive and cause disease in immunocompromised hosts. During mammalian pathogenesis, all pathogenic microbes are exposed to rapidly changing oxygen levels. Oxygen is the critical electron acceptor in aerobic respiration and organisms must possess alternative mechanisms to deal with low oxygen (hypoxic) conditions found at sites of infection in vivo. Our hypothesis is that A. fumigatus utilizes an alcohol fermentation pathway to survive inflammatory responses found in vivo in pulmonary invasive aspergillosis. This hypothesis is founded on preliminary data from metabolomics studies of A. fumigatus infected murine broncheoalveolar lavages showing the production of ethanol in vivo during fungal infections. We are exploring whether this alcohol fermentation pathway is important for A. fumigatus to cause disease by creating genetic mutants of A. fumigatus deficient in their ability to respond to low oxygen conditions via the use of an alcohol fermentation pathway. We currently have identified the genes and generated mutants deficient in these genes that are involved in alcohol fermentation in A. fumigatus. In the past year, we have examined the ability of these alcohol deficient strains for fungal virulence and found that loss of alcohol fermentation does not affect the virulence capability of A. fumigatus. Additional mechanisms of electron transport under hypoxic conditions are the likely explanation for this result and are currently being explored. The results of this proposal have potential clinical significance via direct manipulation of oxygen levels at sites of fungal infection and also the potential to generate increased efficacy of current antifungal drugs.