Using Comparative Genomics to identify Coccidioides Virulence Factors

环境真菌病原菌球孢子虫和组织胞浆菌被提出为 战剂，因为它们容易获得，孢子稳定，感染 气雾化(Casadevall和Pirofski，2006)；从而更多地了解了 这些密切相关的生物对生物防御至关重要。这些生物中的每一个都会转化为 哺乳动物从土壤中吸入具有感染性的孢子后寄生的寄生形式。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 操控主人。为此，我们建议两位研究人类的生物学家合作。 致病真菌，真菌进化生物学方面的经验(约翰·泰勒，加州大学伯克利分校)和 在真菌分子和发育分子生物学方面有经验的人(加州大学安妮塔·西尔分校)。 使用比较基因组学方法分析球虫和组织胞浆很可能 由于它们在进化上的密切关系和生活方式的相似性，它们是富有成果的 土壤和宿主。我们将利用这些生物基因组中固有的信息 病原体和相关真菌产生一套最有可能影响疾病的基因。这 比较方法将揭示在这些基因中经历了强正向选择的基因 真菌病原体。此外，我们还将鉴定球虫和组织胞浆中的保守基因。 它们在每个有机体向寄生形式的转化中都有牵连，因为它们在 组织胞浆体。这些研究将使我们能够对可测试的候选毒力进行优先排序 将评估其在球虫和球虫小鼠模型致病性中的作用的基因 组织胞浆感染。此外，这些研究将确定特定的生物体目标 诊断、治疗和疫苗接种，因此旨在与球虫密切接触 马克·奥尔巴赫和约翰·加尔吉亚尼提出的项目。

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.