A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis.
A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis.
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DOI：
10.1016/j.ebiom.2018.09.029
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发表时间：
2018-10
期刊：
影响因子：
11.1
通讯作者：
Mottram JC
中科院分区：
文献类型：
--
作者：
Carnielli JBT;Crouch K;Forrester S;Silva VC;Carvalho SFG;Damasceno JD;Brown E;Dickens NJ;Costa DL;Costa CHN;Dietze R;Jeffares DC;Mottram JC
米替福辛在印度已成功用于治疗内脏利什曼病（VL），但在巴西的一项临床试验中未能成功治疗内脏利什曼病。为了确定预测VL治疗失败的分子标记，对来自治愈和复发患者的26株婴儿乳杆菌进行了全基因组测序，对snp、基因和染色体拷贝数变异进行了GWAS分析。发现遗传稳定的乳杆菌婴儿米特福辛敏感位点（MSL）的存在与对米特福辛治疗的积极反应之间存在很强的相关性（p = 0.0005）。当分离株没有MSL时，治疗失败的风险增加9.4倍（95% CI 2.11 - 53.54）。MSL完全缺失预测米替福辛失败的敏感性为0.92 (95% CI 0.65 - 0.996)，特异性为0.78 （95% CI 0.52 - 0.92）。对婴儿乳杆菌（n = 157）的基因分型调查显示，MSL的发生频率从巴西东北部的95%到东南部的<5%不等。MSL在所有来自旧大陆（n = 671）的婴儿乳杆菌和多诺瓦氏乳杆菌测序分离株的基因组中被发现，其中米替福辛的治愈率高于93%。了解婴儿乳杆菌中MSL的存在或不存在将允许在治疗前对患者进行分层，有助于建立更好的VL治疗策略。CNPq， FAPES， GCRF MRC和Wellcome Trust。
Miltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil. To identify molecular markers that predict VL treatment failure whole genome sequencing of 26 L. infantum isolates, from cured and relapsed patients allowed a GWAS analysis of SNPs, gene and chromosome copy number variations. A strong association was identified (p = 0·0005) between the presence of a genetically stable L. infantumMiltefosine Sensitivity Locus (MSL), and a positive response to miltefosine treatment. The risk of treatment failure increased 9·4-fold (95% CI 2·11–53·54) when an isolate did not have the MSL. The complete absence of the MSL predicted miltefosine failure with 0·92 (95% CI 0·65–0·996) sensitivity and 0·78 (95% CI 0·52–0·92) specificity. A genotyping survey of L. infantum (n = 157) showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. The MSL was found in the genomes of all L. infantum and L. donovani sequenced isolates from the Old World (n = 671), where miltefosine can have a cure rate higher than 93%. Knowledge on the presence or absence of the MSL in L. infantum will allow stratification of patients prior to treatment, helping to establish better therapeutic strategies for VL treatment. CNPq, FAPES, GCRF MRC and Wellcome Trust.
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影响因子：
6.4
作者：
Dumetz F;Imamura H;Sanders M;Seblova V;Myskova J;Pescher P;Vanaerschot M;Meehan CJ;Cuypers B;De Muylder G;Späth GF;Bussotti G;Vermeesch JR;Berriman M;Cotton JA;Volf P;Dujardin JC;Domagalska MA
通讯作者：
Domagalska MA
影响因子：
12.3
作者：
Ubeda JM;Légaré D;Raymond F;Ouameur AA;Boisvert S;Rigault P;Corbeil J;Tremblay MJ;Olivier M;Papadopoulou B;Ouellette M
通讯作者：
Ouellette M
影响因子：
14.9
作者：
Leprohon P;Légaré D;Raymond F;Madore E;Hardiman G;Corbeil J;Ouellette M
通讯作者：
Ouellette M
影响因子：
4.9
作者：
Pérez-Victoria, JM;Pérez-Victoria, FJ;Gamarro, F
通讯作者：
Gamarro, F
影响因子：
9.8
作者：
Ubeda, Jean-Michel;Raymond, Frederic;Ouellette, Marc
通讯作者：
Ouellette, Marc