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Article(id=1256263563476349159, tenantId=1146029695717560320, journalId=1255847803461844995, issueId=1256263559323967535, articleNumber=null, orderNo=null, doi=10.13346/j.mycosystema.250107, pmid=null, cstr=32115.14.j.mycosystema.250107, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1744128000000, receivedDateStr=2025-04-09, revisedDate=null, revisedDateStr=null, acceptedDate=1748188800000, acceptedDateStr=2025-05-26, onlineDate=1777446173781, onlineDateStr=2026-04-29, pubDate=1771689600000, pubDateStr=2026-02-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1777446173781, onlineIssueDateStr=2026-04-29, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1777446173781, creator=13701087609, updateTime=1777446173781, updator=13701087609, issue=Issue{id=1256263559323967535, tenantId=1146029695717560320, journalId=1255847803461844995, year='2026', volume='45', issue='2', pageStart='250058', pageEnd='250280', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1777446172791, creator=13701087609, updateTime=1777447435276, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1256268854674710546, tenantId=1146029695717560320, journalId=1255847803461844995, issueId=1256263559323967535, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1256268854678904851, tenantId=1146029695717560320, journalId=1255847803461844995, issueId=1256263559323967535, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=250107, endPage=, ext={EN=ArticleExt(id=1256263567263805685, articleId=1256263563476349159, tenantId=1146029695717560320, journalId=1255847803461844995, language=EN, title=Research progress on chromosomal aneuploidy in the mechanism of fungal drug-resistance, columnId=1256263566726934769, journalTitle=Mycosystema, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Fungal drug-resistance poses a serious threat to global public health, with mechanisms encompassing genetic mutations, epigenetic regulation, and genomic instability. Chromosomal aneuploidy has recently emerged as a critical driver of resistance. This review comprehensively summarizes the molecular mechanisms by which aneuploidy mediates resistance in pathogenic fungi, including gene dosage effects, transcriptional dysregulation, and metabolic pathway interference. Key findings reveal that Candida albicans upregulates efflux pump genes (CDR1/2) through chromosomal duplication, while Aspergillus fumigatus reduces azole susceptibility via cyp51A copy number amplification. In Cryptococcus neoformans, stress-induced aneuploidy exhibits dynamic plasticity, rapidly emerging under drug pressure and reverting upon withdrawal. Technologies such as whole genome sequencing (WGS) and qPCR have proven pivotal to be for clinical resistance prediction and therapeutic monitoring, yet cost and technical barriers hinder their widespread implementation. Future research should focus on deciphering the interplay between aneuploidy, epigenetic modifications, and mutational accumulation, alongside developing therapeutic strategies to correct aneuploidy and optimize rapid diagnostics for precision of medicine application. By synthesizing cross-species evidence, this review advances our understanding of fungal resistance mechanisms and informs the development of novel interventions.

, correspAuthors=Xiaodong WANG, authorNote=null, correspAuthorsNote=
*E-mail:
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真菌耐药性已成为全球公共卫生领域的重大挑战，其机制涉及基因突变、表观遗传调控及基因组不稳定性等多重因素。近年来，染色体非整倍体现象在耐药性形成中的作用备受关注。本文系统综述了非整倍体通过基因剂量效应、转录调控改变及代谢途径干扰等机制驱动病原真菌耐药的分子基础。研究表明，白色念珠菌通过染色体重复上调外排泵基因(CDR1/2)，烟曲霉通过cyp51A基因拷贝数增加降低药物敏感性；隐球菌中特定染色体的非整倍化可快速形成并随药物压力动态变化，体现其作为适应性策略的可塑性。全基因组测序(WGS)、qPCR等技术为临床耐药性预测与治疗监测提供了关键手段，但成本与时效性仍限制其转化应用。未来需解析非整倍体与表观遗传、突变累积的协同作用，开发靶向纠正非整倍体的治疗策略，并优化快速检测技术以指导精准用药。本文通过整合多物种研究进展，为深入理解真菌耐药机制及开发新型干预手段提供了理论依据。

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A: 60% of the key research on aneuploidy in Saccharomyces cerevisiae is centered around the responses to metabolic stress, such as that caused by drugs and oxidative stress. B: Genomic rearrangements such as translocations of chromosome arms, mutations in genes such as PDR1, ERG11, TAC1, etc. to produce equal-armed chromosomes, and replication of chromosome trisomes to form new chromosomes. C: Different concentrations of FLC facilitating the first colony appearance, showing the colonies taking longer time to appear at higher FLC concentrations; BFA-induced ER stress induced aneuploid resistance. D: Duplicate gene expression in the Aspergillus fumigatus cyp51A region leads to drug resistance; Duplicate gene expression in the Aspergillus fumigatus cyp51A region leads to resistance; fragmentary duplications in Chr8 and Chr3. E: Chromosome 7E fragment introduced into wheat to further induce chromosome-specific aneuploidy, which in turn alters crop yield, enhances disease resistance, and improves drought tolerance.

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真菌耐药机制中的染色体非整倍体现象研究进展
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钱晶晶 , 王晓东 *
菌物学报 | 综述 2026,45(2): 250107
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菌物学报 | 综述 2026, 45(2): 250107
真菌耐药机制中的染色体非整倍体现象研究进展
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钱晶晶, 王晓东*
作者信息
  • 新疆医科大学第一附属医院，新疆 乌鲁木齐 830054
Research progress on chromosomal aneuploidy in the mechanism of fungal drug-resistance
Jingjing QIAN, Xiaodong WANG*
Affiliations
  • The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang, China
出版时间: 2026-02-22 doi: 10.13346/j.mycosystema.250107
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真菌耐药性已成为全球公共卫生领域的重大挑战，其机制涉及基因突变、表观遗传调控及基因组不稳定性等多重因素。近年来，染色体非整倍体现象在耐药性形成中的作用备受关注。本文系统综述了非整倍体通过基因剂量效应、转录调控改变及代谢途径干扰等机制驱动病原真菌耐药的分子基础。研究表明，白色念珠菌通过染色体重复上调外排泵基因(CDR1/2)，烟曲霉通过cyp51A基因拷贝数增加降低药物敏感性；隐球菌中特定染色体的非整倍化可快速形成并随药物压力动态变化，体现其作为适应性策略的可塑性。全基因组测序(WGS)、qPCR等技术为临床耐药性预测与治疗监测提供了关键手段，但成本与时效性仍限制其转化应用。未来需解析非整倍体与表观遗传、突变累积的协同作用，开发靶向纠正非整倍体的治疗策略，并优化快速检测技术以指导精准用药。本文通过整合多物种研究进展，为深入理解真菌耐药机制及开发新型干预手段提供了理论依据。

真菌耐药性  /  染色体非整倍体  /  基因组不稳定性  /  耐药机制  /  烟曲霉

Fungal drug-resistance poses a serious threat to global public health, with mechanisms encompassing genetic mutations, epigenetic regulation, and genomic instability. Chromosomal aneuploidy has recently emerged as a critical driver of resistance. This review comprehensively summarizes the molecular mechanisms by which aneuploidy mediates resistance in pathogenic fungi, including gene dosage effects, transcriptional dysregulation, and metabolic pathway interference. Key findings reveal that Candida albicans upregulates efflux pump genes (CDR1/2) through chromosomal duplication, while Aspergillus fumigatus reduces azole susceptibility via cyp51A copy number amplification. In Cryptococcus neoformans, stress-induced aneuploidy exhibits dynamic plasticity, rapidly emerging under drug pressure and reverting upon withdrawal. Technologies such as whole genome sequencing (WGS) and qPCR have proven pivotal to be for clinical resistance prediction and therapeutic monitoring, yet cost and technical barriers hinder their widespread implementation. Future research should focus on deciphering the interplay between aneuploidy, epigenetic modifications, and mutational accumulation, alongside developing therapeutic strategies to correct aneuploidy and optimize rapid diagnostics for precision of medicine application. By synthesizing cross-species evidence, this review advances our understanding of fungal resistance mechanisms and informs the development of novel interventions.

fungal resistance  /  chromosomal aneuploidy  /  genomic instability  /  resistance mechanism  /  Aspergillus fumigatus
钱晶晶, 王晓东. 真菌耐药机制中的染色体非整倍体现象研究进展. 菌物学报, 2026 , 45 (2) : 250107 - . DOI: 10.13346/j.mycosystema.250107
Jingjing QIAN, Xiaodong WANG. Research progress on chromosomal aneuploidy in the mechanism of fungal drug-resistance[J]. Mycosystema, 2026 , 45 (2) : 250107 - . DOI: 10.13346/j.mycosystema.250107
正文
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真菌耐药性的产生严重威胁着全球公共卫生安全，给临床治疗带来巨大挑战。近年来，染色体非整倍体现象在真菌耐药机制中的重要性逐渐凸显，成为研究热点。基于新一代测序技术的分析表明，真菌耐药性可通过关键基因的单一突变、多基因突变的累积、转录组变化及染色体非整倍体(如复制)等机制产生(Boyce 2023)。全基因组测序和突变分析的最新进展还表明，基因组的大规模改变，例如倍性(染色体组的数量)的变化，是真菌适应环境胁迫和产生唑类抗性的常见机制(Almeida et al. 2007；Selmecki et al. 2008；Sionov et al. 2010；Ford et al. 2015)。
1 染色体非整倍体在不同真菌中的研究现状
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1.1 酿酒酵母菌
染色体非整倍体作为基因组不稳定的主要形式，在真核生物中广泛存在。以酿酒酵母菌Saccharomyces cerevisiae为模型的研究揭示了非整倍体对细胞代谢和适应性的双重影响，为理解病原真菌的进化机制提供了重要参考(图1A)。酿酒酵母菌作为遗传研究的模式生物，具备生长周期短、基因组注释完整、重组系统高效及单/二倍体稳定等特点(Duina et al. 2014)，为研究非整倍体机制提供了理想模型。目前酿酒酵母菌非整倍体方面的主要研究在对代谢压力(如药物、氧化应激)的响应方面约占60%，例如，酵母基因组在应激期间变得不稳定，这通常会导致适应性非整倍体，从而快速激活恢复细胞稳态的保护机制(Fisher et al. 2022)、在巯基-过氧化物酶缺乏症的响应中，细胞通过染色体(Chr) Ⅺ的复制增加抵消氧化应激的基因的表达(Kaya et al. 2015)；此外酿酒酵母菌非整倍体方面与基因组不稳定性相关的研究约占30%、在合成生物学或工业菌株优化中的应用约占10%。Yona et al. (2012)的研究表明，适应性非整倍体形成在压力选择下可能是有益的，并且经常被细胞用作通过改变染色体拷贝数来上调保护基因的机制。酿酒酵母非整倍体耐药性研究为理解真核生物基因组不稳定性的进化意义提供了独特视角，尽管目前关于非整倍体研究的文献有限，但以耐药性为核心的研究仍在继续，并进一步整合机制与临床应用，故酿酒酵母已被广泛用于评估药物和环境污染物的一种模式菌株(Calabrese 2017)。
1.2 念珠菌属
在人类病原真菌中，念珠菌属Candida的非整倍体现象尤为突出。白色念珠菌C. albicans通过染色体拷贝数变异发展出对唑类药物的耐药性，成为医院感染防控的重大挑战。近期对白色念珠菌和新型隐球菌的研究表明，涉及含有关键唑类抗性基因的重复染色体区域的非整倍性是人类真菌病原体中可能的抗性机制(Selmecki et al. 2010；Chang et al. 2018) (图1B)，暴露唑类药物后，一种或多种非整倍体(染色体重复)会迅速形成，然而，当由于适应性降低而去除唑类时，正常倍性会重新建立(Sionov et al. 2010；Morrow & Fraser 2013；Chang et al. 2018)；还有研究显示，耐药菌株常出现染色体臂的易位、部分染色体区域的重复[如含有ERG11和TAC1的chr5左臂重复产生等臂染色体i (5L)]、染色体三体(如chr3、chr4、chr5或chr7三体)及特定区域的杂合性缺失，以及通过包含着丝粒的片段的复制和端粒末端的添加形成新染色体等基因组重排现象(Coste et al. 2006；Selmecki et al. 2006, 2008；Dunkel et al. 2008；Poláková et al. 2009；Selmecki et al. 2009；Ahmad et al. 2013；Ford et al. 2015；Whaley & Rogers 2016；Anderson et al. 2017；Todd et al. 2019；Kukurudz et al. 2022；Mba et al. 2022)。这些变化可导致相关基因(如CDR1、CDR2、CRZ1和MRR1等)剂量增加，从而增强对唑类药物的耐药性(Todd et al. 2019)。虽然 ERG11和PDR1等单基因突变是念珠菌属耐药的主要原因，但其他真菌种属的大部分临床分离株缺乏ERG11依赖性耐药机制，而是在许多基因中具有累积突变，以产生多基因耐药表型(Boyce 2023)。
1.3 隐球菌属
除念珠菌外，隐球菌和烟曲霉Aspergillus fumigatus中非整倍体的形成与毒力调控和环境适应密切相关，提示这一现象在病原真菌中的广泛进化意义。隐球菌病是由新型隐球菌Cryptococcus neoformans和格特隐球菌复合体Cryptococcus gattii complex引起的一种机会性且可能致命的感染，影响免疫功能低下和免疫功能正常的人群，已成为全球主要的公共卫生问题(Zhou et al. 2022)。有研究在对氟康唑(fluconazole, FLC)表现出异质耐药性的新型隐球菌菌株中获得非整倍体，发现菌株H99连续暴露于高浓度的氟康唑导致不同染色体的二倍体逐步积累(Chr1二倍体，然后是Chr1二倍体加Chr4二倍体，然后是额外的Chr10二倍体，有或没有Chr14二倍体) (Sionov et al. 2010)。然而，在Yang et al. (2021)研究中，H99直接暴露于不同浓度的FLC中，直到出现第一个菌落，在较高的FLC浓度下，菌落出现需要更长的时间。这可能是因为细胞周期进程的停滞是剂量依赖性的，值得注意的是，一些核型导致氟康唑MICs高于选择性条件，例如，在32 μg/mL FLC选择下，单独的Chr4二倍体和Chr4二倍体加Chr1的节段二倍体出现在32 μg/mL FLC选择下，并能够在高达64 μg/mL的FLC中生长，而Chr1、2、4、5、10和14的一个分离二倍体出现在64 μg/mL氟康唑选择下，并且能够在高达128 μg/mL的FLC中生长，因此，一些非整倍体核型不是逐步增加耐药性，而是在单个选择性步骤中提高了FLC耐受性。全基因组测序显示许多抗真菌耐药的临床分离株具有永久性非整倍体，暴露于唑类的新型隐球菌临床分离株通常具有1号染色体二体性，从而导致唑类耐药(Sionov et al. 2010；Semighini et al. 2011；Stone et al. 2019；Zhou et al. 2022)。Zhang et al. (2024)研究首次证明布雷菲德菌素 A (BFA，一种内酯抗生素，是蛋白质运输的特定抑制剂)诱导的内质网(ER)应激有可能通过新型隐球菌的非整倍体引起对抗真菌药物的耐药性，AFR1的过表达赋予对BFA的耐药性，而AFR1的缺失会导致超敏反应，并且主要选择新型隐球菌中的特定和瞬时非整倍体(Chr1x2或Chr3x2)，Chr1x2同时上调与对无关药物耐药相关的多个基因，从而引起交叉耐药。隐球菌的非整倍体形成和其毒力与环境适应性关系密切且危害严重。对氟康唑异质耐药的新型隐球菌菌株有非整倍体，其耐药性有逐步积累和单步提高情况，临床分离株多有永久性非整倍体，BFA可致交叉耐药，表明非整倍体在病原真菌耐药机制中扮演关键角色，其形成机制和导致耐药的方式复杂多样(图1C)。这不仅增加了临床治疗隐球菌感染的难度，也提示我们需进一步探究非整倍体与耐药性的关系。
1.4 曲霉属
烟曲霉Aspergillus fumigatus是曲霉菌病的主要病原体，这种疾病影响全球超过1 000万人，每年导致0.65万人死亡(Bongomin et al. 2017；Latgé & Chamilos 2019)。真菌中的非整倍性是一种经过充分研究的现象(Upshall 1971；Storchova 2018)。Khateb et al. (2023)对来自慢性肺曲霉病(chronic pulmonary aspergillosis, CPA)的16株耐唑类烟曲霉分离株进行了测序，以评估基因组重排，16个CPA分离株中有7株(43.75%)显示出基因组重复，而18个侵入性分离株中则为零，导致该基因表达上调，包括cyp51A在内的区域重复增加了基因表达，进而表明非整倍性是产生唑类耐药的机制(图1D)。在黄曲霉Aspergillus flavus中，Barda et al. (2023)的研究表明，在暴露于高于MIC水平唑类药物(如伏立康唑，voriconazole, VRC)下，菌株可通过特定染色体的非整倍体变化产生耐药，黄曲霉菌株很快就会产生对VRC 具有抗性的克隆。这些克隆在无药物培养基中反复转移后失去了抵抗力，抗性克隆的全基因组测序揭示了一些克隆中8号染色体(Chr8)的重复和3号染色体(Chr3)的片段性重复，且耐药克隆在无药培养基上多次传代后，染色体可恢复正常状态，体现了这种非整倍体介导的耐药具有一定的可塑性。
1.5 镰孢菌与耶氏酵母菌
在非病原真菌中，也有最新研究表明外源染色体片段整合，通过染色体工程将黑麦等近缘物种的抗病基因(如抗镰孢菌头枯病的7E染色体片段)导入小麦，运用着丝粒介导的技术创建植物小染色体，通过编辑着丝粒组蛋白CENH3，成功创制单倍体诱导系(如小麦中敲除TaCENH3基因)，显著提高单倍体诱导率(达8%)，进一步诱导染色体特异性非整倍体(如单体或三体)，进而改变作物产量、增强抗病性、提高耐旱性并解决全球农业面临的许多问题(Liu et al. 2025) (图1E)。与酿酒酵母相比，非常规酵母-耶氏酵母Yarrowia lipolytica具有更大的基因组、更高的GC含量、分散的5S核糖体RNA基因(Gaillardin et al. 2013；Vierna et al. 2013；Luttermann et al. 2021)、信号识别颗粒型7SL RNA序列(Ullu et al. 1982；He et al. 1990)、更高比例的非编码区(Dujon et al. 2004；Yan & Bu 2021)以及各种转座因子的存在(Pomraning et al. 2018；Luttermann et al. 2021)，工业生物技术中的关键酵母Y. lipolytica在自发和诱变条件下的非整倍体发生规律，表明其基因组稳定性受修复机制和选择压力的双重调控，与S. cerevisiae相比，Y. lipolytica的非整倍体频率较低，但诱变剂(如 UV)可显著提高染色体重排风险，提示环境压力对基因组进化的重要影响(Xiong et al. 2025)。目前镰孢菌Fusarium和耶氏酵母菌Yarrowia的非整倍体研究为农业抗性管理和工业方面生物技术应用提供了新思路。
2 染色体非整倍体导致真菌耐药的机制
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2.1 基因剂量效应
染色体非整倍体导致耐药基因拷贝数增加，是产生耐药的重要原因之一。例如在烟曲霉中cyp51A基因重复，使其表达量上升，增强了对唑类药物的抵抗能力。在白念珠菌中，CDR1和 CDR2等外排泵基因所在染色体区域的重复，导致这些基因表达上调，促进药物外排，降低细胞内药物浓度，从而产生耐药性。
2.2 转录调控改变
非整倍体可能影响转录因子结合位点或调控元件的数量及分布，进而改变基因转录水平。在烟曲霉中，一些调控麦角甾醇(ergosterol)生物合成基因(如cyp51A)转录的因子(如SrbA、AtrR等)与染色体非整倍体区域相关联，其表达或结合活性可能因染色体变化而改变，间接影响耐药相关基因的表达(Chang et al. 2007；Willger et al. 2008；Khateb et al. 2023)。在白念珠菌中，Upc2 等转录因子在非整倍体介导的耐药中也发挥关键作用，其功能异常可导致ERG11等基因表达失调，促进耐药性产生(Vu et al. 2021)。
2.3 代谢途径干扰
染色体非整倍体可能影响真菌细胞内多条代谢途径的平衡。在抗真菌药物作用下，真菌通过改变代谢途径来适应药物胁迫，非整倍体可能增强这种适应性。例如，在棘白菌素类(echinocandin)药物耐药机制中，虽然主要由 FKS 基因突变引起，但在部分真菌中染色体非整倍体可能通过影响细胞壁合成相关基因表达或代谢流的改变，协同促进耐药表型的产生(Boyce 2023)。最近一项研究利用光滑梭菌实验进化产生了121个耐阿尼芬净，有趣的是，所有121个菌株在FKS基因中都携带非同义突变，突变优先发生在FKS2中，而不是FKS1 (Ksiezopolska et al. 2021)，但具体分子机制仍有待进一步深入研究。
3 检测染色体非整倍体的方法
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3.1 全基因组测序
全基因组测序(whole genome sequencing, WGS)可系统性检测染色体非整倍体，通过比对测序数据与参考基因组，精确分析拷贝数变异(CNV)及非整倍体区域。通过对真菌基因组进行深度测序，将测序覆盖区域中涉及的关键基因及其拷贝数变化精准定位及识别。在多篇研究中，如对曲霉属、念珠菌属和隐球菌等真菌耐药株的研究，均采用WGS技术揭示了染色体非整倍体现象及其与耐药的关联，例如：WGS技术揭示了真菌耐药性不仅由单基因突变驱动，还可能通过多基因突变的积累(多基因表型)产生，尤其在新型隐球菌和烟曲霉中，耐药性与ERG11非依赖性机制相关(Boyce 2023)；WGS组测序和突变分析的最新进展还表明，基因组的大规模改变，如倍性(染色体集的数量)的变化，是真菌用来适应环境应激和产生唑类耐药性的常见机制(Almeida et al. 2007；Selmecki et al. 2008；Sionov et al. 2010；Ford et al. 2015)。此外Barda et al. (2023)通过WGS制备的基因组DNA，在抗性SS1R0.25L和SS1R1L菌株的基因组中，证实了Chr8上基因的拷贝数是位于Chr6 (未重复的对照)上基因的两倍，强调了非整倍体介导的耐药机制的潜在多样性。Khateb et al. (2023)也通过WGS对16株来自慢性肺曲霉病(CPA)的耐唑烟曲霉分离株测序评估基因组重排，结果显示cyp51A的区域复制会增加基因表达，研究表明非整倍体是CPA中唑类耐药的机制，这些例子都证明了WGS为深入研究提供了关键数据。
3.2 定量PCR
qPCR (quantitative PCR)可用于验证特定基因或染色体区域的拷贝数变化。通过设计针对目标基因或区域的特异性引物，与内参基因对比，定量分析基因拷贝数。在研究黄曲霉耐药株染色体8和3上基因的拷贝数变化时(Barda et al. 2023)，qPCR被用于进一步确认全基因组测序结果，为非整倍体的存在提供了补充证据，且具有操作相对简便、成本较低的优点，在初步验证和大规模样本筛查中具有一定应用价值。
3.3 比较基因组杂交
CGH (comparative genomic hybridization)技术可在全基因组水平检测样本与对照基因组之间的DNA拷贝数差异。将待测真菌DNA与正常参考DNA分别标记不同荧光后进行杂交，通过分析荧光强度比值来确定染色体区域的扩增或缺失情况。虽然目前在真菌研究中应用相对较少且相关文献支持不多，但在其他生物医学辅助诊断领域相关染色体异常研究中具有重要地位，如Kowalczyk et al. (2022)研究在生殖医学方面辅助鉴定早期妊娠流产的染色体异常原因、Johnson et al. (2023)对高危早期扩张型心肌病基因的鉴定，为真菌染色体非整倍体检测提供了一种可参考的技术手段。
4 染色体非整倍体现象的临床意义
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4.1 耐药性预测
通过检测真菌染色体非整倍体状态，可预测其对特定抗真菌药物的耐药性，为临床治疗方案调整提供依据。例如，在烟曲霉感染中，若检测到cyp51A基因所在区域的染色体重复，可高度怀疑其对唑类药物耐药，应考虑选择其他类型抗真菌药物进行治疗(Fisher et al. 2022)。
4.2 治疗监测
在抗真菌治疗过程中，持续监测真菌染色体非整倍体状态可评估治疗效果。若治疗有效，原本存在的非整倍体可能逐渐减少至恢复正常；反之，若非整倍体持续存在或出现新的变化，可能预示着治疗失败或耐药性进一步发展，需要及时采取替代治疗策略(Sionov et al. 2010；Morrow & Fraser 2013；Chang et al. 2018；Boyce 2023)。这为临床治疗提供了一种动态监测指标，有助于优化治疗过程，提高患者预后。
5 未来研究方向
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5.1 深入探究分子机制
尽管目前对染色体非整倍体导致真菌耐药的机制有一定了解，但仍存在许多未知环节。未来需进一步研究非整倍体如何精确调控基因表达网络(如转录及翻译后水平对蛋白质功能及代谢的影响)，以及与其他耐药机制(如基因突变、表观遗传修饰等在不同真菌物种中的保守性和特异性机制)之间的相互作用关系，这些将有助于全面揭示真菌耐药的分子基础。虽然开发了用于检测烟曲霉CYP51A突变的其他内部和商业分子方法，但尚未在临床样本中对其进行评估，对此类工具的适用性提出了挑战(Fisher et al. 2022)。
5.2 开发新型检测技术
现有的检测方法虽然有效，但在临床应用中仍存在一定局限性，如对从曲霉菌病患者中连续收集的分离株测序及全基因组测序有助于揭示感染过程中的突变、识别耐药突变及检测病原物种，但临床实施全基因组测序面临成本高、时间长、生物信息学分析复杂且资源常不在现场、计算工具和数据库不成熟等挑战，虽分析方法已就绪，但从学术研究到临床应用仍有诸多问题需解决(Fisher et al. 2022)。因此，开发快速、准确、低成本且适用于临床实验室的新型染色体非整倍体检测技术至关重要。
5.3 靶向治疗研究
染色体非整倍体相关的耐药机制，探索新型靶向治疗策略是未来研究的重要方向。目前文献中还没有相关研究领域涉及真菌非整倍体耐药的靶向治疗，靶向干预非整倍体形成或耐药相关通路的小分子抑制剂，可能通过修复基因组异常或抑制耐药基因表达，为临床干预提供潜在策略。例如，设计针对参与非整倍体形成或维持的关键蛋白或调控因子的小分子抑制剂，或者利用基因编辑技术修复因非整倍体导致的基因异常，为克服真菌耐药提供新的治疗手段，改善真菌感染患者的临床结局。
6 展望
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染色体非整倍体现象在真菌耐药机制中扮演着重要角色，在多种致病真菌中均有发现，并通过多种机制导致耐药性产生。这些复杂的突变谱与高度可塑性的基因组(其中非整倍性短暂或永久地快速产生)和转录变化相结合，必须将其与适应性反应分开，了解导致耐药性出现的因素对于制定有效的治疗策略至关重要(Boyce 2023)。目前已建立了一系列检测方法，且其在临床耐药性预测和治疗监测方面具有重要意义。然而，仍需在分子机制、检测技术和靶向治疗等方面开展深入研究，以应对日益严峻的真菌耐药问题，为优化抗真菌治疗策略及开发精准干预手段奠定理论基础。
作者贡献
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钱晶晶：论文撰写及修改；王晓东：论文指导及修改。
利益冲突声明
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该研究不存在任何潜在利益冲突的商业或财务关系。
基金
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  • 新疆维吾尔自治区天山英才医疗卫生中青年骨干高层次人才培养计划(TSYC202301B029)
  • 新疆维吾尔自治区自然科学杰出青年基金(2021D01E30)
文献
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2026年第45卷第2期
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doi: 10.13346/j.mycosystema.250107
  • 接收时间：2025-04-09
  • 首发时间：2026-04-29
  • 出版时间：2026-02-22
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  • 收稿日期：2025-04-09
  • 录用日期：2025-05-26
基金
Xinjiang Uygur Autonomous Region Tianshan Talent Medical and Health Care High-level Talent Training Program for Young and Middle-aged Key Talents(TSYC202301B029)
新疆维吾尔自治区天山英才医疗卫生中青年骨干高层次人才培养计划(TSYC202301B029)
Xinjiang Uygur Autonomous Region Natural Science Foundation for Outstanding Youth(2021D01E30)
新疆维吾尔自治区自然科学杰出青年基金(2021D01E30)
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    新疆医科大学第一附属医院，新疆 乌鲁木齐 830054

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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