In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis.
In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis.
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DOI：
10.1016/j.fgb.2018.02.003
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Warris A
中科院分区：
文献类型：
--
作者：
Ballard E;Melchers WJG;Zoll J;Brown AJP;Verweij PE;Warris A
A.的宿主内适应描述烟曲霉促进真菌的持久性。在13个连续的A.从一个病人身上分离出烟曲霉菌。新出现的唑类耐药性，真菌生长，分生孢子和毒力的差异。在整个系列中开发了248个非同义单核苷酸多态性。为了生存，烟曲霉必须适应特定的生态位环境。对人类宿主的适应包括促进持久定殖和唑类耐药性发展的修饰。本研究的目的是进一步了解A.患者在感染和治疗期间的烟曲霉菌感染。十三A烟曲霉菌株分离自患有持续和复发的侵袭性曲霉病超过2年的单个慢性肉芽肿病患者。所有菌株具有相同的微卫星基因型，被认为是等基因的。全基因组比较确定了248个非同义单核苷酸多态性。这些非同义突变有可能在宿主适应中发挥作用。前2个菌株对唑类药物敏感，而后面的菌株对伊曲康唑、伏立康唑和/或泊沙康唑耐药。在存在和不存在各种抗真菌应激物的情况下的生长测定突出了生长速率和应激抗性的微小变化，除了一个分离株显示出显著的生长缺陷。在后来的分离物中观察到不良的分生孢子。在某些耐药菌株中，在伊曲康唑的存在下恢复分生孢子。如在大蜡螟感染模型中所示，观察到毒力差异。我们认为，A.烟曲霉在该患者中的感染已经驱动了Cyp 51 A非依赖性和Cyp 51 A依赖性、唑类耐药机制以及可能促进真菌持久性的其他表型的出现。
Description of in-host adaptation of A. fumigatus promoting fungal persistence. Significant in-host microevolution was identified in 13 consecutive A. fumigatus isolates from a single patient. Emerging azole resistance, fungal growth, conidiation and virulence differences were observed. 248 non-synonymous single nucleotide polymorphisms developed throughout series. In order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence.
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影响因子：
14.9
作者：
Flicek P;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt S;Johnson N;Juettemann T;Kähäri AK;Keenan S;Kulesha E;Martin FJ;Maurel T;McLaren WM;Murphy DN;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ruffier M;Sheppard D;Taylor K;Thormann A;Trevanion SJ;Vullo A;Wilder SP;Wilson M;Zadissa A;Aken BL;Birney E;Cunningham F;Harrow J;Herrero J;Hubbard TJ;Kinsella R;Muffato M;Parker A;Spudich G;Yates A;Zerbino DR;Searle SM
通讯作者：
Searle SM
影响因子：
--
作者：
Amich, Jorge;Vicentefranqueira, Rocio;Antonio Calera, Jose
通讯作者：
Antonio Calera, Jose
影响因子：
4.9
作者：
Garcia-Effron, G;Mellado, E;Rodriguez-Tudela, JL
通讯作者：
Rodriguez-Tudela, JL
影响因子：
5.2
作者：
Chen, J;Li, HM;Wan, Z
通讯作者：
Wan, Z
影响因子：
4.9
作者：
Denning, DW;Venkateswarlu, K;Kelly, SL
通讯作者：
Kelly, SL