Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the Democratic Republic of the Congo.
Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the Democratic Republic of the Congo.
复制标题
DOI：
10.1371/journal.pntd.0003212
复制
发表时间：
2014-10-01
影响因子：
3.8
通讯作者：
Buscher, Philippe
中科院分区：
文献类型：
--
作者：
Pyana Pati, Patient;Van Reet, Nick;Buscher, Philippe
背景：布鲁氏锥虫(T.B.)引起的昏睡病冈比亚构成撒哈拉以南非洲的一个严重的健康问题。在一些病灶中，使用美拉索洛尔治疗的患者复发率高得惊人，这曾是神经系统疾病阶段患者的一线治疗方法。特别有问题的是刚果民主共和国东开赛省姆布吉-马伊的情况，其复发率为57%，而班顿杜省马西-马尼巴的复发率为5%。本研究旨在利用最近分离的结核分枝杆菌的扩展集合来研究姆布吉-玛伊地区高复发率背后的机制。Mbuji-Mayi和Masi-Manimba的冈比亚菌株.方法/主要发现：45株T.B.使用冈比亚菌株。在Mbuji-Mayi，从美拉索治疗后治愈或复发的患者中分离出41例。体内药物敏感性测试提供了这些菌株对美拉索敏感性降低的证据。美拉索洛尔敏感性的降低与TbAT1基因突变无关。然而，在所有这些菌株中，无论患者的治疗结果如何，两个水甘油磷脂(AQP)2和3基因被嵌合的AQP2/3基因取代，这可能与对戊二胺和美拉索的耐药性有关。The 4 T.B.在马西-马尼巴分离的冈比亚菌株既含有野生型AQP2，又含有不同的嵌合体AQP2/3。这些发现表明，Mbuji-Mayi菌株体内对美拉索的敏感性降低和昏睡病疫源地的高复发率是由AQP2/AQP3基因突变而不是TbAT1突变引起的。结论：我们得出结论：TbAQP2/3基因座的突变是当地T.B.冈比亚菌株可能解释了Mbuji-Mayi病灶中美拉索复发率高的原因，但个别患者的治疗结果也必须涉及其他因素。
BACKGROUND: Sleeping sickness caused by Trypanosoma brucei (T.b.) gambiense constitutes a serious health problem in sub-Sahara Africa. In some foci, alarmingly high relapse rates were observed in patients treated with melarsoprol, which used to be the first line treatment for patients in the neurological disease stage. Particularly problematic was the situation in Mbuji-Mayi, East Kasai Province in the Democratic Republic of the Congo with a 57% relapse rate compared to a 5% relapse rate in Masi-Manimba, Bandundu Province. The present study aimed at investigating the mechanisms underlying the high relapse rate in Mbuji-Mayi using an extended collection of recently isolated T.b. gambiense strains from Mbuji-Mayi and from Masi-Manimba.METHODOLOGY/PRINCIPAL FINDINGS: Forty five T.b. gambiense strains were used. Forty one were isolated from patients that were cured or relapsed after melarsoprol treatment in Mbuji-Mayi. In vivo drug sensitivity tests provide evidence of reduced melarsoprol sensitivity in these strains. This reduced melarsoprol sensitivity was not attributable to mutations in TbAT1. However, in all these strains, irrespective of the patient treatment outcome, the two aquaglyceroporin (AQP) 2 and 3 genes are replaced by chimeric AQP2/3 genes that may be associated with resistance to pentamidine and melarsoprol. The 4 T.b. gambiense strains isolated in Masi-Manimba contain both wild-type AQP2 and a different chimeric AQP2/3. These findings suggest that the reduced in vivo melarsoprol sensitivity of the Mbuji-Mayi strains and the high relapse rates in that sleeping sickness focus are caused by mutations in the AQP2/AQP3 locus and not by mutations in TbAT1.CONCLUSIONS/SIGNIFICANCE: We conclude that mutations in the TbAQP2/3 locus of the local T.b. gambiense strains may explain the high melarsoprol relapse rates in the Mbuji-Mayi focus but other factors must also be involved in the treatment outcome of individual patients.