Genomic Diversity of Azole-Resistant Aspergillus fumigatus in the United States.
Genomic Diversity of Azole-Resistant Aspergillus fumigatus in the United States.
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DOI：
10.1128/mbio.01803-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Litvintseva AP
中科院分区：
文献类型：
--
作者：
Etienne KA;Berkow EL;Gade L;Nunnally N;Lockhart SR;Beer K;Jordan IK;Rishishwar L;Litvintseva AP
致病性烟曲霉（Aspergillus fumigatus）对唑的耐药性已成为威胁医用唑使用的全球性公共卫生问题。环境发生的耐药突变TR34/L98H （TR34）和TR46/Y121F/T289A （TR46）广泛分布于多个大洲，并在美国出现。我们使用全基因组单核苷酸多态性（SNP）分析了179个具有全国代表性的来自美国和18个非美国的烟熏菌临床和环境基因组。以评估美国出现的唑类耐药的遗传多样性和基础。我们证实了烟抽沙螨分离株的进化支的存在：进化支A（17%）由全球临床和环境中抗唑菌株组成，包括来自印度、荷兰、英国和美国的所有具有TR34/L98H等位基因的菌株，进化支B（83%）由主要来自美国的不含该标记的分离株组成。TR34/L98H多态性在印度、荷兰、英国和美国的耐唑烟曲霉菌株中普遍存在，提示该耐药机制具有共同的起源。具有TR34抗性标记的美国耐唑烟曲霉分离株中，6%含有a支和B支混合等位基因，提示存在重组。此外，两种交配类型的比例相等，进一步表明重组的持续存在。本研究证明了美国出现唑类抗性的遗传背景，支持单次引种和随后的繁殖，可能是通过环境驱动抗性突变的重组。
Azole resistance in pathogenic Aspergillus fumigatus has become a global public health issue threatening the use of medical azoles. The environmentally occurring resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), are widespread across multiple continents and emerging in the United States. We used whole-genome single nucleotide polymorphism (SNP) analysis on 179 nationally represented clinical and environmental A. fumigatus genomes from the United States along with 18 non-U.S. genomes to evaluate the genetic diversity and foundation of the emergence of azole resistance in the United States. We demonstrated the presence of clades of A. fumigatus isolates: clade A (17%) comprised a global collection of clinical and environmental azole-resistant strains, including all strains with the TR34/L98H allele from India, The Netherlands, the United Kingdom, and the United States, and clade B (83%) consisted of isolates without this marker mainly from the United States. The TR34/L98H polymorphism was shared among azole-resistant A. fumigatus strains from India, The Netherlands, the United Kingdom, and the United States, suggesting the common origin of this resistance mechanism. Six percent of azole-resistant A. fumigatus isolates from the United States with the TR34 resistance marker had a mixture of clade A and clade B alleles, suggestive of recombination. Additionally, the presence of equal proportions of both mating types further suggests the ongoing presence of recombination. This study demonstrates the genetic background for the emergence of azole resistance in the United States, supporting a single introduction and subsequent propagation, possibly through recombination of environmentally driven resistance mutations.