乌干达高传播地区多个地理位置的恶性疟原虫群体中青蒿素部分抗药性标记(pfk13 突变)的新威胁。

IF 2.4 3区 医学 Q3 INFECTIOUS DISEASES
Bosco B Agaba, Jye Travis, David Smith, Simon P Rugera, Maria G Zalwango, Jimmy Opigo, Charles Katureebe, Ruth Mpirirwe, Dembo Bakary, Martin Antonio, Beshir Khalid, Joseph Ngonzi, Moses R Kamya, Pontiano Kaleebu, Peter Piot, Qin Cheng
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引用次数: 0

摘要

背景:青蒿素类复方疗法(ACT)目前被推荐用于治疗无并发症疟疾。然而,部分青蒿素抗药性的出现和传播威胁着青蒿素综合疗法在疟疾负担最重的撒哈拉以南非洲地区治疗疟疾的有效性。及早检测和报告恶性疟原虫的有效分子标记(pfk13 突变)有助于追踪部分青蒿素抗药性的出现和传播,为遏制工作提供信息:从 2021 年 6 月到 2023 年 8 月,在乌干达卡拉莫贾、兰戈、阿乔利和西尼罗河四个地区的 50 个监测点进行了基因组监测。招募有症状的疟疾疑似患者并对其进行寄生虫筛查。此外,还收集了干血斑 (DBS),以便通过 PCR 和测序进行寄生虫基因组分析。在 563 个可用的干血斑(DBS)中,随机挑选了 240 个经多重 PCR 确认的恶性疟原虫单体感染子集,并使用大染液终结者方法进行 Sanger 测序,检测 pfk13 突变。pfk13 突变比例的区域差异采用卡方检验(chi square)或费雪精确检验(Fisher's exact tests)进行评估,而野生型寄生虫和突变型寄生虫之间寄生虫 DNA 绝对水平的比较则采用 Kruskal-Wallis 检验:总体而言,238/240 个样本(99.2%)含有足够的 DNA 并成功测序。在测序的样本中发现了三种突变:32/238(13.5%)个样本中发现了 pfk13 C469Y,14/238(5.9%)个样本中发现了 pfk13 A675V,在四个调查地区的 1/238(0.42%)个样本中发现了 pfk13 S522C。卡拉莫贾地区的 pfk13 C469Y 突变率(23.3%)明显高于其他地区,P = 0.007。西尼罗河地区流行的大多数寄生虫分离株都是野生型(98.3),P = 0.002。携带野生型、C469Y 和 A675V 等位基因的样本中寄生虫 DNA 的相对数量没有差异(Kruskal-Wallis 检验,P = 0.6373):在这种情况下,在多个地理位置检测到青蒿素部分抗药性的有效分子标记,为乌干达新出现的青蒿素部分抗药性威胁提供了更多证据。鉴于这些发现,建议定期进行基因组监测,在检测TES的同时检测和监测其他地区的pfk13突变水平,以评估在这种情况下对寄生虫清除延迟和相关治疗失败的潜在影响。未来的研究应考虑确定乌干达不同疟疾传播环境中青蒿素部分抗药性的潜在驱动因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Emerging threat of artemisinin partial resistance markers (pfk13 mutations) in Plasmodium falciparum parasite populations in multiple geographical locations in high transmission regions of Uganda.

Background: Artemisinin-based combination therapy (ACT) is currently recommended for treatment of uncomplicated malaria. However, the emergence and spread of partial artemisinin resistance threatens their effectiveness for malaria treatment in sub-Saharan Africa where the burden of malaria is highest. Early detection and reporting of validated molecular markers (pfk13 mutations) in Plasmodium falciparum is useful for tracking the emergence and spread of partial artemisinin resistance to inform containment efforts.

Methods: Genomic surveillance was conducted at 50 surveillance sites across four regions of Uganda in Karamoja, Lango, Acholi and West Nile from June 2021 to August 2023. Symptomatic malaria suspected patients were recruited and screened for presence of parasites. In addition, dried blood spots (DBS) were collected for parasite genomic analysis with PCR and sequencing. Out of 563 available dried blood spots (DBS), a random subset of 240 P. falciparum mono-infections, confirmed by a multiplex PCR were selected and used for detecting the pfk13 mutations by Sanger sequencing using Big Dye Terminator method. Regional variations in the proportions of pfk13 mutations were assessed using the chi square or Fisher's exact tests while Kruskal-Wallis test was used to compare absolute parasite DNA levels between wild type and mutant parasites.

Results: Overall, 238/240 samples (99.2%) contained sufficient DNA and were successfully sequenced. Three mutations were identified within the sequenced samples; pfk13 C469Y in 32/238 (13.5%) samples, pfk13 A675V in 14/238 (5.9%) and pfk13 S522C in (1/238 (0.42%) samples across the four surveyed regions. The prevalence of pfk13 C469Y mutation was significantly higher in Karamoja region (23.3%) compared to other regions, P = 0.007. The majority of parasite isolates circulating in West Nile are of wild type (98.3), P = 0.002. Relative parasite DNA quantity did not differ in samples carrying the wild type, C469Y and A675V alleles (Kruskal-Wallis test, P = 0.6373).

Conclusion: Detection of validated molecular markers of artemisinin partial resistance in multiple geographical locations in this setting provides additional evidence of emerging threat of artemisinin partial resistance in Uganda. In view of these findings, periodic genomic surveillance is recommended to detect and monitor levels of pfk13 mutations in other regions in parallel with TES to assess potential implication on delayed parasite clearance and associated treatment failure in this setting. Future studies should consider identification of potential drivers of artemisinin partial resistance in the different malaria transmission settings in Uganda.

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来源期刊
Malaria Journal
Malaria Journal 医学-寄生虫学
CiteScore
5.10
自引率
23.30%
发文量
334
审稿时长
2-4 weeks
期刊介绍: Malaria Journal is aimed at the scientific community interested in malaria in its broadest sense. It is the only journal that publishes exclusively articles on malaria and, as such, it aims to bring together knowledge from the different specialities involved in this very broad discipline, from the bench to the bedside and to the field.
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