Muñoz José F, Gauthier Gregory M, Desjardins Christopher A, Gallo Juan E, Holder Jason, Sullivan Thomas D, Marty Amber J, Carmen John C, Chen Zehua, Ding Li, Gujja Sharvari, Magrini Vincent, Misas Elizabeth, Mitreva Makedonka, Priest Margaret, Saif Sakina, Whiston Emily A, Young Sarah, Zeng Qiandong, Goldman William E, Mardis Elaine R, Taylor John W, McEwen Juan G, Clay Oliver K, Klein Bruce S, Cuomo Christina A
Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia; Institute of Biology, Universidad de Antioquia, Medellín, Colombia.
Department of Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
PLoS Genet. 2015 Oct 6;11(10):e1005493. doi: 10.1371/journal.pgen.1005493. eCollection 2015 Oct.
Three closely related thermally dimorphic pathogens are causal agents of major fungal diseases affecting humans in the Americas: blastomycosis, histoplasmosis and paracoccidioidomycosis. Here we report the genome sequence and analysis of four strains of the etiological agent of blastomycosis, Blastomyces, and two species of the related genus Emmonsia, typically pathogens of small mammals. Compared to related species, Blastomyces genomes are highly expanded, with long, often sharply demarcated tracts of low GC-content sequence. These GC-poor isochore-like regions are enriched for gypsy elements, are variable in total size between isolates, and are least expanded in the avirulent B. dermatitidis strain ER-3 as compared with the virulent B. gilchristii strain SLH14081. The lack of similar regions in related species suggests these isochore-like regions originated recently in the ancestor of the Blastomyces lineage. While gene content is highly conserved between Blastomyces and related fungi, we identified changes in copy number of genes potentially involved in host interaction, including proteases and characterized antigens. In addition, we studied gene expression changes of B. dermatitidis during the interaction of the infectious yeast form with macrophages and in a mouse model. Both experiments highlight a strong antioxidant defense response in Blastomyces, and upregulation of dioxygenases in vivo suggests that dioxide produced by antioxidants may be further utilized for amino acid metabolism. We identify a number of functional categories upregulated exclusively in vivo, such as secreted proteins, zinc acquisition proteins, and cysteine and tryptophan metabolism, which may include critical virulence factors missed before in in vitro studies. Across the dimorphic fungi, loss of certain zinc acquisition genes and differences in amino acid metabolism suggest unique adaptations of Blastomyces to its host environment. These results reveal the dynamics of genome evolution and of factors contributing to virulence in Blastomyces.
芽生菌病、组织胞浆菌病和副球孢子菌病。在此，我们报告了芽生菌病病原体芽生菌属（Blastomyces）的四个菌株以及相关的埃蒙斯菌属（Emmonsia）两个物种的基因组序列及分析，埃蒙斯菌属通常是小型哺乳动物的病原体。与相关物种相比，芽生菌属的基因组高度扩展，具有长的、通常界限分明的低GC含量序列区域。这些富含吉普赛元件的低GC等容线样区域在不同分离株之间的总大小可变，并且与有毒力的吉尔克里斯特芽生菌（B. gilchristii）菌株SLH14081相比，无毒力的皮炎芽生菌（B. dermatitidis）菌株ER - 3中这些区域的扩展程度最小。相关物种中缺乏类似区域表明这些等容线样区域是最近在芽生菌属谱系的祖先中起源的。虽然芽生菌属与相关真菌之间的基因含量高度保守，但我们确定了可能参与宿主相互作用的基因拷贝数变化，包括蛋白酶和已鉴定的抗原。此外，我们研究了皮炎芽生菌在感染性酵母形式与巨噬细胞相互作用期间以及在小鼠模型中的基因表达变化。两个实验都突出了芽生菌中强烈的抗氧化防御反应，并且体内双加氧酶的上调表明抗氧化剂产生的二氧化物可能进一步用于氨基酸代谢。我们确定了一些仅在体内上调的功能类别，如分泌蛋白、锌获取蛋白以及半胱氨酸和色氨酸代谢，这可能包括以前在体外研究中遗漏的关键毒力因子。在整个双态真菌中，某些锌获取基因的缺失以及氨基酸代谢的差异表明芽生菌属对其宿主环境有独特的适应性。这些结果揭示了芽生菌属基因组进化的动态以及导致其毒力的因素。
