Glans Hedvig, Matos Gabriel M, Bradley Maria, Downing Tim, Andersson Björn
Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
Division of Dermatology and Venerology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2024 Dec 3;19(12):e0310821. doi: 10.1371/journal.pone.0310821. eCollection 2024.
Cutaneous leishmaniasis caused by L. tropica is common in the Middle East and treatment failure and drug resistance are known to occur. Several genetic mechanisms: aneuploidy, recombination and loss of heterozygosity, single nucleotide polymorphism (SNP) changes, copy number variation (CNV), and mutation of the H locus associated with drug resistance have been described.
We studied SNP and CNV patterns in 22 isolates of L. tropica from Afghanistan, Iran and Syria in a geographic, phylogenetic and antimony exposure context.
A high SNP frequency was observed in isolates from Syria on chromosome 23, including the H locus, linked to different ancestry at that chromosome segment. Among the isolates from Afghanistan and Iran, an elevated frequency of nonsynonymous SNPs was observed on several chromosomes. Changes in CNV patterns were seen in isolates exposed to drug pressure, especially for the ferric iron reductase gene. Expanded genes were categorised into five functional categories: translational elongation, mitochondrial transmembrane transport, positive regulation of cellular component organisation, response to stimulus and response to hypoxia. No CNV was identified at the H locus, the MAPK1 gene, the APQ1 gene, nor chromosomes 23, 31 or 36 regardless of previous antimonial exposure.
In our study, Leishmania tropica had a jump in the nonsynonymous SNP rates at chromosome 23, including the H locus. CNV was observed among isolates exposed to antimonials, especially involving the gene encoding a ferric iron reductase. Several essential genetic coping mechanisms in the cell were enhanced when exposed to antimony, possibly for the survival of the parasite. Our work supports the perspective that Leishmania uses several mechanisms to adapt to environmental changes and drug exposure.
由热带利什曼原虫引起的皮肤利什曼病在中东地区很常见，已知会出现治疗失败和耐药情况。已经描述了几种遗传机制：非整倍体、重组和杂合性丧失、单核苷酸多态性（SNP）变化、拷贝数变异（CNV）以及与耐药性相关的H位点突变。
我们在地理、系统发育和锑暴露背景下，研究了来自阿富汗、伊朗和叙利亚的22株热带利什曼原虫的SNP和CNV模式。
在来自叙利亚的分离株中，23号染色体上观察到高SNP频率，包括与该染色体片段不同祖先相关的H位点。在来自阿富汗和伊朗的分离株中，在几条染色体上观察到非同义SNP频率升高。在受到药物压力的分离株中观察到CNV模式的变化，特别是对于铁还原酶基因。扩展基因被分为五个功能类别：翻译延伸、线粒体跨膜转运、细胞成分组织的正调控、对刺激的反应和对缺氧的反应。无论先前是否接触过锑，在H位点、MAPK1基因、APQ1基因以及23、31或36号染色体上均未发现CNV。
在我们的研究中，热带利什曼原虫在23号染色体（包括H位点）的非同义SNP率出现跃升。在接触锑的分离株中观察到CNV，特别是涉及编码铁还原酶的基因。当暴露于锑时，细胞中的几种重要遗传应对机制可能会增强，这可能是为了寄生虫的生存。我们的工作支持了利什曼原虫利用多种机制适应环境变化和药物暴露的观点。
