MLST and Whole-Genome-Based Population Analysis of Cryptococcus gattii VGIII Links Clinical, Veterinary and Environmental Strains, and Reveals Divergent Serotype Specific Sub-populations and Distant Ancestors.
MLST and Whole-Genome-Based Population Analysis of Cryptococcus gattii VGIII Links Clinical, Veterinary and Environmental Strains, and Reveals Divergent Serotype Specific Sub-populations and Distant Ancestors.
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DOI：
10.1371/journal.pntd.0004861
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发表时间：
2016-08
影响因子：
3.8
通讯作者：
Meyer W
中科院分区：
文献类型：
--
作者：
Firacative C;Roe CC;Malik R;Ferreira-Paim K;Escandón P;Sykes JE;Castañón-Olivares LR;Contreras-Peres C;Samayoa B;Sorrell TC;Castañeda E;Lockhart SR;Engelthaler DM;Meyer W
新出现的病原体加特隐球菌会在免疫功能正常和免疫功能低下的宿主中引起危及生命的疾病。在四种主要分子类型（VGI-VGIV）中，分子类型VGIII最近已成为健康个体的疾病原因，这促使需要研究其群体遗传结构，以了解其流行病学，环境生态位，宿主范围和疾病的临床特征中是否存在潜在的基因型依赖性特征。对122株临床、环境和兽医用C.来自澳大利亚、哥伦比亚、危地马拉、墨西哥、新西兰、巴拉圭、美国和委内瑞拉的gattii VGIII分离株，以及代表所有已建立MLST类型的60个分离株的全基因组测序（WGS）鉴定了四个不同的亚群。大多数分离株属于两个主要分支，对应于血清型B或C，表明正在进行的物种进化。两个主要分支包括临床、环境和兽医分离株。梭Gattii VGIII种群遗传多样性很高，在国家、分离源、血清型和交配型之间存在微小差异。在全基因组和线粒体基因组水平上，在两个主要组（血清型B和C）之间几乎没有发现重组。C.加特VGIII在美洲广泛分布，其他地方也有零星病例，WGS发现墨西哥和美国可能是血清型B VGIII人群的来源，哥伦比亚可能是血清型C VGIII人群的来源。在小鼠感染模型中，血清型B分离株比血清型C分离株毒力更强，主要引起肺隐球菌病。没有观察到基因型和毒力之间的特定联系。对6种抗真菌药物的抗真菌药敏试验显示，血清型B分离株比血清型C分离株对唑类药物更敏感，强调了菌株分型对指导有效治疗以改善疾病结局的重要性。格特隐球菌（Cryptococcus gattii）是隐球菌病的第二重要病因，其经典地分为四种主要分子型（VGI-VGIV）和两种血清型B和C。由分子类型VGIII引起的人类和动物隐球菌病病例的发病率上升突出了提高警惕的必要性。在这项研究中，我们描述了一个大的C。格特氏VGIII分离株。遗传分析显示了四个不同的亚群，它们主要与血清型B或C相关，并且很可能起源于哥伦比亚、墨西哥和美国的流行地区。血清型之间的毒力和抗真菌药敏性差异可能导致不同的疾病结果，因为血清型B分离株在小鼠中的毒力比血清型C分离株更强，但血清型C分离株对唑类药物不太敏感，唑类药物是无并发症隐球菌病的主要治疗药物。在临床实践中，隐球菌血清型和分子类型的鉴定有可能指导治疗方案，从而降低散发病例和与暴发相关病例的发病率和死亡率。我们的研究对隐球菌和隐球菌病的流行病学、遗传学和发病机制的了解有重要意义。
The emerging pathogen Cryptococcus gattii causes life-threatening disease in immunocompetent and immunocompromised hosts. Of the four major molecular types (VGI-VGIV), the molecular type VGIII has recently emerged as cause of disease in otherwise healthy individuals, prompting a need to investigate its population genetic structure to understand if there are potential genotype-dependent characteristics in its epidemiology, environmental niche(s), host range and clinical features of disease. Multilocus sequence typing (MLST) of 122 clinical, environmental and veterinary C. gattii VGIII isolates from Australia, Colombia, Guatemala, Mexico, New Zealand, Paraguay, USA and Venezuela, and whole genome sequencing (WGS) of 60 isolates representing all established MLST types identified four divergent sub-populations. The majority of the isolates belong to two main clades, corresponding either to serotype B or C, indicating an ongoing species evolution. Both major clades included clinical, environmental and veterinary isolates. The C. gattii VGIII population was genetically highly diverse, with minor differences between countries, isolation source, serotype and mating type. Little to no recombination was found between the two major groups, serotype B and C, at the whole and mitochondrial genome level. C. gattii VGIII is widespread in the Americas, with sporadic cases occurring elsewhere, WGS revealed Mexico and USA as a likely origin of the serotype B VGIII population and Colombia as a possible origin of the serotype C VGIII population. Serotype B isolates are more virulent than serotype C isolates in a murine model of infection, causing predominantly pulmonary cryptococcosis. No specific link between genotype and virulence was observed. Antifungal susceptibility testing against six antifungal drugs revealed that serotype B isolates are more susceptible to azoles than serotype C isolates, highlighting the importance of strain typing to guide effective treatment to improve the disease outcome. Cryptococcus gattii, which is classically divided into four major molecular types (VGI-VGIV), and two serotypes B and C, is the second most important cause of cryptococcosis. The rising incidence of human and animal cryptococcosis cases caused by molecular type VGIII highlights the need for increased vigilance. In this study, we characterized a large set of C. gattii VGIII isolates. Genetic analysis revealed four diverging sub-populations, which were primarily associated with serotype B or C, and very likely originated from endemic regions in Colombia, Mexico and the USA. Differences in virulence and antifungal susceptibility between serotypes may result in different disease outcomes since serotype B isolates were more virulent in mice than serotype C isolates, but serotype C isolates were less susceptible to azoles, the primary treatment for uncomplicated cryptococcosis. Identification of cryptococcal serotype and molecular type in clinical practice has the potential to guide treatment regimens and hence reduce morbidity and mortality in both sporadic cases and those associated with outbreaks. Our study significantly contributes to the understanding of the epidemiology, genetics and pathogenesis of Cryptococcus and cryptococcosis.