A Phylogenetic Approach to Virulence in Aspergillus

描述(由申请人提供)：侵袭性曲霉病(IA)是一种严重的，通常是致命的，免疫功能低下的患者的感染。最常见的病原体烟曲霉和黄曲霉在环境中很常见，但目前还不清楚是否所有的菌株都同样可能导致IA。这两种真菌的基因组最近都被测序，许多基因被确定为潜在的毒力贡献者。该项目的长期目标是识别与毒力有关的基因，追踪环境种群和临床分离株之间的关系，并确定霉菌毒素的产生是否使分离株更有可能导致IA。这一建议的独特之处在于，它采用了系统发生学的方法来研究IA的毒力。它由五个相互关联的特定目标组成：1)确定烟曲霉和黄曲霉的所有分支是否都同样有可能导致侵袭性曲霉病，或者临床分离株是否仅限于某些支系；2)通过比较基于每个基因的系统发育和基于中性标记的系统发育，识别潜在的致病基因；3)确定引起侵袭性曲霉病的烟曲霉和黄曲霉分离株是否普遍产生真菌毒素；以及4)使用微阵列识别可能与侵袭性曲霉病相关的其他基因；5)重新引导PI的研究计划，将重点放在人类病原体和基因组学上。将进化生物学和来自基因组学的信息整合起来，应用于严重的病原体，这与NIH和NIAID的使命是一致的。 相关性：由于新药的使用，IA的死亡率有所下降，但在某些人群中仍有60%。主要病原菌烟曲霉和黄曲霉是环境中常见的机会性腐生细菌。两者都会产生剧毒的霉菌毒素，尽管它们在IA中的作用尚不清楚。然而，由黄曲霉及其相关物种产生的黄曲霉毒素对世界各地的公共健康构成严重威胁，最近爆发的疫情导致非洲数百人死亡。更好地了解哪些基因与毒力有关，哪些环境人口可能导致IA，这可能会导致拯救许多人生命的策略。

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is a serious, frequently fatal, infection of immunocompromised patients. The most common pathogens, Aspergillus fumigatus and A. flavus, are common in the environment, but it is not clear if all isolates are equally likely to cause IA. The genomes of both fungi have recently been sequenced, and many genes have been identified as potential contributors to virulence. The long-term objective of this project is to identify genes involved in virulence, trace relationships between environmental populations and clinical isolates, and establish whether mycotoxin production makes an isolate more likely to cause IA. This proposal is unique in that it takes a phylogenetic approach to study virulence in IA. It consists of five interrelated Specific Aims: 1) Establish whether members of all clades of A. fumigatus and A. flavus are equally likely to cause invasive aspergillosis, or whether clinical isolates are restricted to certain clades; 2) Identify genes potentially involved in virulence by comparing phylogenies based on each gene with phylogenies based on neutral markers; 3) Establish whether mycotoxin production is prevalent in isolates of A. fumigatus and A. flavus that cause invasive aspergillosis; and 4) Identify other genes that may be associated with invasive aspergillosis using microarrays; 5) Redirect the Pi's research program to focus on human pathogens and genomics.. The proposed integration of evolutionary biology and information from genomics, applied to a serious pathogen, is consonant with NIH's and NIAID's mission. Relevance: Mortality from IA has decreased thanks to new drugs, but is still >60% in some groups. The main pathogens, A. fumigatus and A. flavus, are opportunistic saprotrophs that are common in the environment. Both produce extremely toxic mycotoxins, though their role in IA is not clearly established. However, aflatoxins, produced by A. flavus and related species, are a serious threat to public health worldwide and recent outbreaks killed hundreds in Africa. Better understanding of which genes contribute to virulence and which environmental populations are likely to cause IA could lead to strategies that may save many lives.