MECHANISMS OF ALCOHOL PATHOGENESIS IN RESPONSE TO HYPOXIA IN A FUMIGATUS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 烟曲霉是一种丝状真菌，是免疫低下患者侵袭性霉菌感染的最常见病原体。目前，我们对烟曲霉菌在免疫功能低下的宿主中存活和致病的机制了解有限。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。氧是有氧呼吸中的关键电子受体，生物体必须具有替代机制来处理感染部位发现的低氧(低氧)条件。我们的假设是，在侵袭性肺曲霉菌病期间，烟曲霉利用酒精发酵途径在体内发现的低氧微环境中存活。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。我们正在通过利用酒精发酵途径产生缺乏对低氧条件反应能力的遗传突变体，来探索这种酒精发酵途径是否对烟曲霉致病很重要。在过去的一年里，我们检测了这些酒精缺乏菌株对真菌毒力的能力，发现酒精发酵的丧失并不影响烟曲霉的致病能力。然而，有趣的是，酒精产生的丧失会导致招募到感染部位的天然免疫效应细胞的类型和数量发生显著变化，此外，乙醇发酵突变株减少了感染小鼠肺部的真菌负荷，这表明酒精发酵的丧失改变了侵袭性肺曲霉菌病的发病机制。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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Aspergillus fumigatus is a filamentous fungus that is the most frequent causal agent of invasive mold infections in immunocompromised patients. We currently have a limited understanding of 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. Our hypothesis is that A. fumigatus utilizes an alcohol fermentation pathway to survive hypoxic microenvironments found in vivo during invasive pulmonary aspergillosis. This hypothesis is founded on preliminary data from metabolomics studies of A. fumigatus infected murine bronchoalveolar 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 generating genetic mutants of A. fumigatus that are deficient in their ability to respond to low oxygen conditions via the use of an alcohol fermentation pathway. 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 capability of A. fumigatus to cause disease. However, intriguingly, loss of ethanol production results in significant changes in the types and numbers of innate immune effector cells that are recruited to the site of infection, Moreover, ethanol fermentation mutants have reduced fungal burden in the lungs of infected mice suggesting that loss of ethanol fermentation alters the pathogenesis of invasive pulmonary aspergillosis. 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.