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议为 战争媒介，因为它们易于获得、孢子稳定性以及感染 雾化（Casadeval 和 Pirofski，2006）；从而对发病机制有更多的了解 这些密切相关的生物体对于生物防御至关重要。这些生物体中的每一个都转化为 哺乳动物宿主吸入土壤中的传染性孢子后形成寄生形式。我们的目标是 通过识别促进疾病的真菌基因来了解这些真菌的发病机制 操纵宿主。为此，我们建议两位研究人类的生物学家进行合作 病原真菌，一位在真菌进化生物学方面经验丰富的人（约翰·泰勒，加州大学伯克利分校）和 一位在真菌分子和发育分子生物学方面经验丰富的人（Anita Sil，UCSF）。 使用比较基因组学方法来分析球孢子菌和组织胞浆菌可能会 由于它们密切的进化关系以及生活方式的相似性，因此能够硕果累累 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。这个 比较方法将揭示在这些基因中经历过强烈正向选择的基因 真菌病原体。此外，我们将鉴定球孢子菌和组织胞浆菌中的保守基因 凭借其在 组织胞浆菌。这些研究将使我们能够优先考虑可测试数量的候选毒力 将评估其在球孢子菌和球孢子菌小鼠模型中的致病性作用的基因 组织胞浆菌感染。此外，这些研究将确定生物体特异性靶标 诊断、治疗和疫苗接种，因此旨在与球孢子菌紧密结合 马克·奥尔巴赫和约翰·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.