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且经常致命的感染。最常见的病原体，烟曲霉和黄曲霉，在环境中很常见，但目前尚不清楚是否所有分离株都有同样的可能引起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潜在的致病因素。该项目的长期目标是确定参与毒力的基因，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引起IA。这一建议的独特之处在于它采用系统发育的方法来研究IA的毒力。它由五个相互关联的特定目的组成：1)确定烟曲霉和黄曲霉的所有分支的成员是否同样可能引起侵袭性曲霉病，或者临床分离是否仅限于某些分支；2)通过比较基于每个基因的系统发生与基于中性标记的系统发生，鉴定可能参与毒力的基因；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霉菌毒素；4)利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的研究项目转向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，这与NIH和NIAID的使命是一致的。

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.