Genetic Diversity of A. fumigatus

描述（由申请方提供）：侵袭性曲霉病（IA）是几种免疫功能低下人群的常见死亡原因。预防IA仍然很困难，部分原因是对感染生物体的生物学和种群结构的了解有限。烟曲霉是IA最常见的病原体，被认为是形态上同源的物种;然而，我们最近的研究表明， 它们在遗传上可能比表型研究所表明的更不均一。采用多位点序列分型（MLST）方法进行系统发育分析。烟曲霉至少由3个遗传上不同的分支组成- A. fumigatus（Clade）和2个以前未被识别的Clades（2和3）。对进化枝2的详细分析表明，这些分离物代表了一个新的物种，目前被命名为A。小扁豆该物种具有临床意义，因为它们在体外和体内对几种抗真菌药物具有相对耐药性，并且在动物模型中具有毒性。因此，由于形态种A.烟曲霉可能由几个临床上重要的隐蔽物种组成，在这个群体中定义不同的群体对于理解IA的发病机制和开发有效的治疗策略是必要的。本文提出的研究将：通过国际筛选确定曲霉属分支3（Aim 1）的流行病学 文化收藏。这个新识别的进化枝3将通过分析表型来表征。 生长、微形态和抗真菌能力等特征。将在IA动物模型中评估毒力潜力。目标2将开发一个强大的MLST计划的表征A。通过从高变的候选基因中组装一组遗传学上有用的基因，对烟曲霉进行鉴定。该MLST方案将用于确定大量A.全球分布的烟曲霉菌株。目的3将开发标记物，用于在临床微生物学实验室中鉴定独特的进化枝，通过采用稳健的算法来鉴定曲霉属进化枝之间潜在有用的生长差异。烟曲霉属）。本文的研究还将开发基于PCRRFLP的方法来快速区分进化枝。这些研究将阐明一种新发现的曲霉菌的临床意义，并将开发一种严格的分子分型方法，以提高我们对真菌病原体A的生物学和种群结构的认识。烟熏。

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is a common cause of mortality in several immunocompromised populations. Prevention of IA remains difficult, in part because of limited understanding of the biology and the population structure of the infecting organisms. Aspergillus fumigatus, the most common etiological agent of IA, is considered to be a morphologically homogenous species; however our recent investigations indicate that they may be genetically more heterogeneous than suggested by phenotypic studies. Phylogenetic analysis using a multi-locus sequence typing (MLST) scheme revealed that A. fumigatus consists of at least 3 genetically distinct clades - A. fumigatus (Clade) and 2 previously unrecognized Clades (2 and 3). Detailed analysis of Clade 2 revealed that these isolates represent a new species, currently designated as A. lentulus. This species is clinically significant as they are relatively resistant to several antifungal drugs both in vitro and in vivo, and are virulent in animal models. Thus, since the morpho-species A. fumigatus may consist of several clinically significant cryptic species, defining distinct groups within this population will be imperative to understand the pathogenesis of IA and to develop effective therapeutic strategies. The studies proposed herein will: Define the epidemiology of the Aspergillus sp. Clade 3 (Aim 1) by screening international culture collections. This newly recognized Clade 3 will be characterized by analyzing phenotypic characteristics such as growth, micro morphology and antifungal susceptibilities. Virulence potential will be assessed in animal models of IA. Aim 2 will develop a robust MLST scheme for the characterization of A. fumigatus by assembling a panel of phylogenetically useful genes from candidate genes that are hypervariable. This MLST scheme will be used to determine the genotypic diversity of a large number of A. fumigatus isolates of worldwide distribution. Aim 3 will develop markers for identification of unique clades in a clinical microbiology laboratory by employing a robust algorithm to identify potentially useful growth differences among Aspergillus clades, (A. fumigatus group). Studies herein will also develop PCRRFLP based methods to rapidly discriminate between clades. The studies proposed will clarify the clinical significance of a newly recognized Aspergillus sp. and will develop a stringent molecular typing method that will enhance our knowledge of the biology and population structure of the fungal pathogen A. fumigatus.