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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 烟曲霉是一种嗜酸性丝状真菌，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A使用的机制。烟曲霉在免疫功能低下的宿主中存活并引起疾病。在哺乳动物发病过程中，所有病原微生物都暴露于快速变化的氧气水平。氧是有氧呼吸中的关键电子受体，生物体必须具有替代机制来处理体内感染部位的低氧（缺氧）条件。我们的假设是A.烟曲霉菌利用酒精发酵途径在肺侵袭性曲霉病体内发现的炎症反应中存活。这一假说是建立在A.烟曲霉感染的小鼠支气管肺泡灌洗液显示在真菌感染期间体内乙醇的产生。我们正在探索这种酒精发酵途径是否对A.烟曲霉通过产生A.烟曲霉缺乏通过使用酒精发酵途径对低氧条件作出反应的能力。目前，我们已经确定了基因，并产生突变体，这些基因缺陷，参与酒精发酵在A。烟熏。在过去的一年里，我们已经检查了这些酒精缺乏菌株的真菌毒力的能力，发现酒精发酵的损失并不影响A。烟熏。缺氧条件下的电子传递的其他机制是这一结果的可能解释，目前正在探索。该建议的结果具有潜在的临床意义，通过直接操纵氧气水平在真菌感染的网站，也有可能产生增加目前的抗真菌药物的疗效。

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.