Using Comparative Genomics to identify Coccidioides Virulence Factors

环境真菌病原体球孢子菌和组织胞浆菌已被提出作为 由于其容易获得，孢子的稳定性和感染性， 雾化（Casadevall和Pirofski，2006）;因此，更多的知识，发病机制， 这些密切相关的生物对生物防御至关重要。每一种微生物都转化为 从土壤中吸入感染性孢子后寄生在哺乳动物宿主体内。我们的目标是 通过鉴定促进疾病的真菌基因来了解这些真菌的发病机制， 操纵主机。为了做到这一点，我们建议两位研究人类的生物学家合作， 病原真菌，一个在真菌进化生物学方面有经验的（约翰·泰勒，加州大学伯克利分校）， 一位在真菌分子和发育分子生物学方面有经验的人（Anita Sil，UCSF）。 使用比较基因组学方法分析球孢子菌和组织胞浆菌可能 由于它们之间密切的进化关系和它们生活方式的相似性， 土壤和宿主我们将利用这些基因组中固有的信息， 病原体和相关真菌产生一组最有可能影响疾病的基因。这 比较的方法将揭示基因已经经历了强阳性选择在这些 真菌病原体此外，我们将确定球孢子菌和组织胞浆菌中的保守基因 它们由于在生物体中的作用而与每种生物体向寄生形式的转化有关， 组织胞浆菌这些研究将使我们能够优先考虑一些可测试的候选毒力 将评估其在球孢子菌属小鼠模型中致病性作用的基因， 组织胞浆菌感染。此外，这些研究将确定生物体的具体目标， 诊断，治疗和疫苗接种，因此被设计为与球孢子菌密切相关 马克·奥巴赫和约翰·加尔贾尼提出的项目。

The environmental fungal pathogens Coccidioides and Histoplasma have been proposed as agents of warfare because of their easy availability, stability of spores, and infection by aerosolization (Casadevall and Pirofski, 2006); thus more knowledge about the pathogenesis of these closely related organisms is critical to biodefense. Each of these organisms converts to a parasitic form in mammalian hosts after inhalation of infectious spores from the soil. We aim to understand pathogenesis of these fungi by identifying fungal genes that promote disease and manipulate the host. To do so, we propose a collaboration between two biologists who study human pathogenic fungi, one experienced in fungal evolutionary biology (John Taylor, UC Berkeley) and one experienced in fungal molecular and developmental molecular biology (Anita Sil, UCSF). Use of a comparative genomics approach to analyze Coccidioides and Histoplasma is likely to be fruitful because of their close evolutionary relationship and the similarities of their lifestyles in the soil and the host. We will take advantage of information inherent in the genomes of these pathogens and related fungi to generate a set of genes most likely to influence disease. This comparative approach will reveal genes that have undergone strong positive selection in these fungal pathogens. Additionally, we will identify conserved genes in Coccidioides and Histoplasma that are implicated in the conversion to the parasitic form of each organism by virtue of their role in Histoplasma. These studies will allow us to prioritize a testable number of candidate virulence genes that will be assessed for their role in pathogenicity in the mouse models of Coccidioides and Histoplasma infection. In addition, these studies will identify organism-specific targets for diagnosis, therapy and vaccination, and thus are designed to interface closely with Coccidioides projects proposed by Marc Orbach and John Galgiani.