Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans
Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans
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DOI：
10.1128/mbio.00595-17
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发表时间：
2017-05-01
期刊：
影响因子：
6.4
通讯作者：
Idnurm, Alexander
中科院分区：
文献类型：
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作者：
Boyce, Kylie J.;Wang, Yina;Idnurm, Alexander
适应不断变化的环境的能力为微生物提供了选择优势。在许多病原体的情况下，当它们从自然环境移动到人类宿主内的环境，然后在疾病发展过程中移动到该宿主内的各个位置时，它们的环境发生了很大的变化。人类真菌病原体新型隐球菌的两个临床分离株是从一系列表现出突变表型的环境和临床菌株中鉴定出来的，突变表型是一种由于DNA突变以高频率积累而提供快速变化能力的表型。这些菌株的全基因组分析揭示了错配修复途径的MSH2突变，互补证实了这些突变是增变子表型的原因。比较8个错配修复途径基因缺失株的突变频率。在新生儿中的研究表明，其中三个基因MSH2、MLH1和PMS1的缺失导致突变率增加。增加的突变率使这些菌株能够发生快速的微进化，产生与体内生长能力相关的性状的表型变异，此外还允许快速产生抗真菌剂的抗性。PMS1的突变降低了毒力，而MSH2或MLH1的突变对毒力水平没有影响。因此，这些发现支持了这样的假设，即这种致病真菌可以利用突变子表型来引起疾病，但它只能在导致突变子性状的特定途径中这样做，而不会在适应性方面进行重大权衡。表面真菌感染影响全球约17亿（25%）的总人口，而系统性真菌疾病导致令人难以接受的高死亡率。真菌如何适应它们的宿主还没有完全了解。这项研究调查了DNA序列变化在适应宿主环境中的作用，以及在世界上最常见和最致命的真菌病原体之一新型隐球菌中引起疾病的能力。研究结果表明，无论是临床分离株还是msh 2突变的基因缺失株，微进化率都有所增强。该基因在调节C的远亲真菌中抗真菌药物抗性的快速出现方面具有相似的功能。新生菌，病原体光滑念珠菌。因此，由增强的突变率导致的微进化可能是真菌发病机制的共同贡献者。
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 Cryptococcus neoformans 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 MSH2 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 C. neoformans showed that the loss of three of them, MSH2, MLH1, and PMS1, 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 vivo, in addition to allowing rapid generation of resistance to antifungal agents. Mutation of PMS1 reduced virulence, whereas mutation of MSH2 or MLH1 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.IMPORTANCE 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 Cryptococcus neoformans, 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 msh2 mutations. This gene has similar functions in regulating the rapid emergence of antifungal drug resistance in a distant fungal relative of C. neoformans, the pathogen Candida glabrata. Thus, microevolution resulting from enhanced mutation rates may be a common contributor to fungal pathogenesis.