来自毛里塔尼亚、苏丹和阿曼的间日疟原虫田间分离株的间日疟原虫metacaspase 1基因和间日疟原虫多药耐药1基因的遗传多样性。

Genetic diversity of Plasmodium vivax metacaspase 1 and Plasmodium vivax multi-drug resistance 1 genes of field isolates from Mauritania, Sudan and Oman.

作者信息

Sow Fatimata, Bonnot Guillaume, Ahmed Bilal Rabah, Diagana Sidi Mohamed, Kebe Hachim, Koita Mohamedou, Samba Ba Malado, Al-Mukhaini Said K, Al-Zadjali Majed, Al-Abri Seif S, Ali Osama A M, Samy Abdallah M, Hamid Muzamil Mahdi Abdel, Ali Albsheer Musab M, Simon Bruno, Bienvenu Anne-Lise, Petersen Eskild, Picot Stéphane

机构信息

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires ICBMS-UMR5246, CNRS-INSA-CPE, Malaria Research Unit, University Claude Bernard Lyon 1, 43 Boulevard du 11 novembre 1918, Lyon, 69622, Villeurbane, France.

Laboratoire de Bactériologie et Parasitologie de l'Hôpital Cheikh Zayed, BP-5720, Nouakchott, Mauritania.

出版信息

Malar J. 2017 Feb 2;16(1):61. doi: 10.1186/s12936-017-1687-1.

DOI:10.1186/s12936-017-1687-1

PMID:28153009

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5288979/

Abstract

BACKGROUND

Plasmodium vivax is the second most important human malaria parasite, widely spread across the world. This parasite is associated with important issues in the process toward malaria elimination, including potential for relapse and increased resistance to chloroquine. Plasmodium vivax multi-drug resistant (pvmdr1) is suspected to be a marker of resistance although definitive evidence is lacking. Progress has been made in knowledge of biological factors affecting parasite growth, including mechanisms of regulated cell death and the suspected role of metacaspase. Plasmodium vivax metacaspase1 (PvMCA1-cd) has been described with a catalytic domain composed of histidine (H372) and cysteine (C428) residues. The aim of this study was to test for a link between the conserved histidine and cysteine residues in PvMCA1-cd, and the polymorphism of the P. vivax multi-drug resistant gene (pvmdr1).

RESULTS

Thirty P. vivax isolates were collected from Mauritania, Sudan, and Oman. Among the 28 P. vivax isolates successfully sequenced, only 4 samples showed the conserved His (372)-Cys (428) residues in PvMCA1-cd. Single nucleotide polymorphisms observed were H372T (46.4%), H372D (39.3%), and C428R (85.7%). A new polymorphic catalytic domain was observed at His (282)-Cys (305) residues. Sequences alignment analysis of pvmdr1 showed SNP in the three codons 958, 976 and 1076. A single SNP was identified at the codon M958Y (60%), 2 SNPs were found at the position 976: Y976F (13%) and Y976V (57%), and 3 SNPs were identified at the position 1076: F1076L (40%), F1076T (53%) and F1076I (3%). Only one isolate was wildtype in all three codons (MYF), 27% were single MYL mutants, and 10% were double MFL mutants. Three new haplotypes were also identified: the triple mutant YVT was most prevalent (53.3%) distributed in the three countries, while triple YFL and YVI mutants (3%), were only found in samples from Sudan and Mauritania.

CONCLUSIONS

Triple or quadruple mutants for metacaspase genes and double or triple mutants for Pvmdr1 were observed in 24/28 and 19/28 samples. There was no difference in the frequency of mutations between PvMCA1-cd and Pvmdr1 (P > 0.2). Histidine and cysteine residues in PvMCA1-cd are highly polymorphic and linkage disequilibrium with SNPs of Pvmdr1 gene may be expected from these three areas with different patterns of P. vivax transmission.

摘要

背景

间日疟原虫是第二重要的人类疟原虫，广泛分布于世界各地。这种寄生虫在疟疾消除进程中引发了重要问题，包括复发的可能性以及对氯喹耐药性的增加。尽管缺乏确凿证据，但间日疟原虫多重耐药性（pvmdr1）被怀疑是耐药性的一个标志。在影响寄生虫生长的生物学因素的认识方面取得了进展，包括程序性细胞死亡机制和类半胱天冬酶的疑似作用。间日疟原虫类半胱天冬酶1（PvMCA1-cd）已被描述为由组氨酸（H372）和半胱氨酸（C428）残基组成的催化结构域。本研究的目的是测试PvMCA1-cd中保守的组氨酸和半胱氨酸残基与间日疟原虫多重耐药基因（pvmdr1）多态性之间的联系。

结果

从毛里塔尼亚、苏丹和阿曼收集了30株间日疟原虫分离株。在成功测序的28株间日疟原虫分离株中，只有4个样本在PvMCA1-cd中显示出保守的His（372）-Cys（428）残基。观察到的单核苷酸多态性为H372T（46.4%）、H372D（39.3%）和C428R（85.7%）。在His（282）-Cys（305）残基处观察到一个新的多态性催化结构域。pvmdr1的序列比对分析显示在958、976和1076这三个密码子中有单核苷酸多态性。在密码子M958Y处鉴定出一个单核苷酸多态性（60%），在976位点发现2个单核苷酸多态性：Y976F（13%）和Y976V（57%），在1076位点鉴定出3个单核苷酸多态性：F1076L（40%）、F1076T（53%）和F1076I（3%）。在所有三个密码子（MYF）中只有一个分离株是野生型，27%是单MYL突变体，10%是双MFL突变体。还鉴定出三种新的单倍型：三重突变体YVT最为普遍（53.3%），分布在这三个国家，而三重YFL和YVI突变体（3%）仅在来自苏丹和毛里塔尼亚的样本中发现。

结论

在24/28和19/28个样本中观察到类半胱天冬酶基因的三重或四重突变体以及Pvmdr1的双突变或三突变体。PvMCA1-cd和Pvmdr1之间的突变频率没有差异（P>0.2）。PvMCA1-cd中的组氨酸和半胱氨酸残基高度多态，从间日疟原虫传播模式不同的这三个地区来看，可能预期它们与Pvmdr1基因的单核苷酸多态性存在连锁不平衡。