School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
Public Health Research Institute, Rutgers University, Newark, New Jersey, USA.
mBio. 2017 May 30;8(3):e00595-17. doi: 10.1128/mBio.00595-17.
The ability to adapt to a changing environment provides a selective advantage to microorganisms. In the case of many pathogens, a large change in their environment occurs when they move from a natural setting to a setting within a human host and then during the course of disease development to various locations within that host. Two clinical isolates of the human fungal pathogen were identified from a collection of environmental and clinical strains that exhibited a mutator phenotype, which is a phenotype which provides the ability to change rapidly due to the accumulation of DNA mutations at high frequency. Whole-genome analysis of these strains revealed mutations in of the mismatch repair pathway, and complementation confirmed that these mutations are responsible for the mutator phenotype. Comparison of mutation frequencies in deletion strains of eight mismatch repair pathway genes in showed that the loss of three of them, , , and , results in an increase in mutation rates. Increased mutation rates enable rapid microevolution to occur in these strains, generating phenotypic variations in traits associated with the ability to grow , in addition to allowing rapid generation of resistance to antifungal agents. Mutation of reduced virulence, whereas mutation of or had no effect on the level of virulence. These findings thus support the hypothesis that this pathogenic fungus can take advantage of a mutator phenotype in order to cause disease but that it can do so only in specific pathways that lead to a mutator trait without a significant tradeoff in fitness. Fungi account for a large number of infections that are extremely difficult to treat; superficial fungal infections affect approximately 1.7 billion (25%) of the general population worldwide, and systemic fungal diseases result in an unacceptably high mortality rate. How fungi adapt to their hosts is not fully understood. This research investigated the role of changes to DNA sequences in adaption to the host environment and the ability to cause disease in , one of the world's most common and most deadly fungal pathogens. The study results showed that microevolutionary rates are enhanced in either clinical isolates or in gene deletion strains with mutations. This gene has similar functions in regulating the rapid emergence of antifungal drug resistance in a distant fungal relative of , the pathogen Thus, microevolution resulting from enhanced mutation rates may be a common contributor to fungal pathogenesis.
适应不断变化的环境的能力为微生物提供了选择优势。对于许多病原体而言，当它们从自然环境转移到人类宿主的环境中，然后在疾病发展过程中转移到宿主的各种位置时，它们的环境会发生很大的变化。从表现出突变表型的环境和临床菌株的集合中鉴定出两种人类真菌病原体的临床分离株，突变表型是指由于高频 DNA 突变的积累而迅速改变的表型。对这些菌株的全基因组分析显示，错配修复途径中有 8 个错配修复途径基因发生了突变，并且互补证实这些突变是突变表型的原因。在 中比较了缺失 8 个错配修复途径基因的菌株的突变频率，结果表明，其中 3 个基因（ 、 、和 ）的缺失会导致突变率增加。突变率的增加使这些菌株能够快速发生微进化，从而导致与生长能力相关的表型变异，此外还能够快速产生对抗真菌药物的抗性。 突变降低了毒力，而 或 突变对毒力水平没有影响。这些发现支持了这样一种假设，即这种致病真菌可以利用突变表型来致病，但它只能在特定的途径中这样做，这些途径会导致突变表型，而不会对适应性造成显著的权衡。真菌引起大量难以治疗的感染；全球约有 17 亿人（25%）患有浅部真菌感染，系统性真菌感染导致的死亡率高得令人无法接受。真菌如何适应其宿主尚不完全清楚。这项研究调查了 DNA 序列变化在适应宿主环境和引起疾病的能力中的作用， 是世界上最常见和最致命的真菌病原体之一。研究结果表明，临床分离株或具有 突变的基因缺失株的微进化率都得到了提高。这个基因在调节另一种真菌病原体 的抗真菌药物耐药性的快速出现方面具有相似的功能。因此，由于突变率提高而导致的微进化可能是真菌病发病机制的一个共同因素。
