Evolution of Aspergillus fumigatus virulence

项目摘要。真菌介导的疾病进展通过形成的真菌细胞群体来突出显示， 一个被称为生物膜的群落。为了治疗成功，当代抗真菌治疗必须 在已建立的真菌生物膜的情况下在感染部位有效。重要的是，现在很清楚， 由真菌生物膜产生的新特性直接改变了毒力、疾病进展和抗真菌作用。 药物敏感性然而，丝状真菌生物膜出现特性的机制 影响毒力、疾病进展和抗真菌药敏感性仍然是一个重大知识缺口。的 本项目的长期目标是确定烟曲霉生物膜的分子机制 介导的疾病进展机制，为当代和新的治疗方法提供信息。在 在前一个资助期，我们取得了重要进展，令人惊讶地揭示了A.烟曲霉 临床分离株的生物膜形态。生物膜形态的差异改变了毒力和疾病 在曲霉菌病小鼠模型中的体内进展。我们发现长期在低氧环境中生长 环境产生了一种生物膜形态，我们称之为H-MORPH，一种新的真菌特异性基因 包含具有未知功能的蛋白质的簇足以形成H-MOPRH。重要的是，我们 从急性侵袭性曲霉病患者和慢性曲霉病患者中鉴定出H-MORPH临床分离株 曲霉病，表明H-MORPH可以在人类疾病中出现。我们观察到H-MOPRH发生在体内 在侵袭性肺曲霉菌病的小鼠模型中， 对比的N-MORPH分离物。在目标1中，我们将定义调节A的遗传途径。烟曲霉 利用新发现的生物膜结构开发这种独特的群体水平形态型 因子（BAF）基因家族作为剖析潜在机制的工具。在目标2中，我们将定义差异 在真菌代谢中，作为N-MORPH和H-MORPH形态型基础，并检验了H-MORPH MORPH生物膜是碳分解代谢物去抑制，其导致体内适应性增加。在目标3中，我们测试 假设H-MORPH菌株代谢是通过真菌病原体中的改变进行免疫调节的， 相关的分子模式暴露。总之，我们提出的研究将填补重要的知识， 与发现不同的A.烟曲霉形态类型直接影响毒力。推进我们 了解这一知识差距有望为新的诊断和治疗奠定基础。 战略，以打击高毒力和耐药菌株，这一重要的人类真菌病原体。

Project Summary. Fungal mediated disease progression is highlighted by populations of fungal cells that form a community referred to as a biofilm. For therapeutic success, contemporary antifungal therapies must be effective at the site of infection in the context of an established fungal biofilm. Critically, it is now clear that emergent properties arise from fungal biofilms that directly alter virulence, disease progression, and antifungal drug susceptibility. However, the mechanisms through which filamentous fungal biofilm emergent properties impact virulence, disease progression, and antifungal susceptibility remain a significant knowledge gap. The long-term goal of this project is focused on defining the molecular mechanisms of Aspergillus fumigatus biofilm mediated disease progression mechanisms to inform contemporary and novel therapeutic approaches. In the prior funding period, we made important progress that surprisingly revealed heterogeneity in A. fumigatus biofilm morphology across clinical isolates. Differences in biofilm morphology altered virulence and disease progression in vivo in murine models of aspergillosis. We discovered that long term growth in a low oxygen environment gives rise to a biofilm morphology we termed H-MORPH and that a novel fungal specific gene cluster that contains a protein with unknown function was sufficient for H-MOPRH formation. Significantly, we identified H-MORPH clinical isolates from both acute invasive aspergillosis patients and patients with chronic aspergillosis, suggesting H-MORPH can arise in human disease. We observed that H-MOPRH occurs in vivo in a murine model of invasive pulmonary aspergillosis and contributes to worse disease outcomes compared to the contrasting N-MORPH isolates. In aim 1, we will define the genetic pathway(s) that regulate A. fumigatus the development of this unique population level morphotype utilizing the newly discovered biofilm architecture factor (baf) gene family as a tool to dissect the underlying mechanisms. In aim 2, we will define the differences in fungal metabolism that underly N-MORPH and H-MORPH morphotypes and test the hypothesis that H- MORPH biofilms are carbon catabolite de-repressed which leads to increased fitness in vivo. In aim 3, we test the hypothesis that H-MORPH strain metabolism is immune modulatory through alterations in fungal pathogen associated molecular pattern exposure. Taken together, our proposed studies will fill significant knowledge gaps related to the discovery of distinct A. fumigatus morphotypes that directly impact virulence. Advancing our understanding of this knowledge gap is expected to lay the foundation for new diagnostic and therapeutic strategies to combat highly virulent and drug resistant strains of this important human fungal pathogen.