A Phylogenetic Approach to Virulence in Aspergillus

描述（由申请人提供）：侵袭性曲霉病（IA）是免疫功能低下患者的一种严重、经常致命的感染。最常见的病原菌为烟曲霉和曲霉。黄曲霉在环境中很常见，但尚不清楚是否所有分离株都同样可能引起IA。这两种真菌的基因组最近已被测序，许多基因已被确定为毒力的潜在贡献者。该项目的长期目标是确定与毒力相关的基因，追踪环境人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容易引起IA。这个建议是独特的，因为它需要一个系统发育的方法来研究毒力IA。它由五个相互关联的具体目标组成：1）确定A. fumigatus和A. 2）通过比较基于每个基因的致病性与基于中性标记的致病性来鉴定可能与毒力有关的基因; 3）确定真菌毒素产生是否在A. fumigatus和A.导致侵袭性曲霉病的黄曲霉; 4）使用微阵列鉴定可能与侵袭性曲霉病相关的其他基因; 5）将Pi的研究计划重新定向为关注人类病原体和基因组学。将进化生物学和基因组学的信息结合起来应用于一种严重的病原体，符合NIH和NIAID的使命。 相关性：由于新药的出现，IA的死亡率有所下降，但在某些人群中仍高于60%。主要病原菌为A. fumigatus和A. flavus是环境中常见的机会性腐养生物。两者都产生毒性极强的真菌毒素，尽管它们在IA中的作用尚不清楚。然而，由A.黄曲霉及其相关物种是对全世界公共卫生的严重威胁，最近的爆发在非洲造成数百人死亡。更好地了解哪些基因有助于毒力和哪些环境人口可能导致IA可能导致的战略，可以挽救许多生命。

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.