Genetic Diversity of A. fumigatus

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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.