Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.
Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.
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DOI：
10.1371/journal.pmed.1000055
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发表时间：
2009-04-14
期刊：
影响因子：
15.8
通讯作者：
Roper C
中科院分区：
文献类型：
--
作者：
Pearce RJ;Pota H;Evehe MS;Bâ el-H;Mombo-Ngoma G;Malisa AL;Ord R;Inojosa W;Matondo A;Diallo DA;Mbacham W;van den Broek IV;Swarthout TD;Getachew A;Dejene S;Grobusch MP;Njie F;Dunyo S;Kweku M;Owusu-Agyei S;Chandramohan D;Bonnet M;Guthmann JP;Clarke S;Barnes KI;Streat E;Katokele ST;Uusiku P;Agboghoroma CO;Elegba OY;Cissé B;A-Elbasit IE;Giha HA;Kachur SP;Lynch C;Rwakimari JB;Chanda P;Hawela M;Sharp B;Naidoo I;Roper C
Cally Roper 及其同事分析了磺胺多辛耐药突变和侧翼微卫星位点的分布，以追踪耐药性恶性疟原虫疟疾在非洲的出现和传播。尽管对多种常见抗疟药物耐药性的分子基础是众所周知的，但尚未尝试对耐药性突变在非洲的出现和传播进行地理描述。为此，我们描述了二氢蝶酸合酶（dhps）基因中抗叶酸剂耐药突变的进化起源，并绘制了它们的当代分布图。我们利用 dhps 基因侧翼的微卫星多态性来确定哪些抗性等位基因具有共同的祖先，并发现了五个主要谱系，每个谱系都有独特的地理分布。 20 个非洲恶性疟原虫群体等位基因谱系的共享程度揭示了五个主要的地理分组。抗性谱系在这些地区的所有地点都很常见。最明显的分化是东非和西非恶性疟原虫之间的差异，其中抗性等位基因不仅具有不同的祖先，而且还携带不同的抗性突变。过去 10-20 年间，抗性 dhps 已在非洲多个地点独立出现。我们的数据显示东非和西非耐药性的分子基础不同，这可能会转化为不同的抗叶酸敏感性。我们还证明，抗性谱系的传播模式为最近的寄生虫迁移模式提供了独特的见解。 恶性疟原虫是一种由蚊子传播的寄生虫，会导致疟疾，每年导致近一百万人死亡，其中大部分发生在撒哈拉以南非洲地区。当人们被蚊子叮咬时，就会感染恶性疟原虫，而蚊子从感染者的血中获得了寄生虫。恶性疟原虫疟疾的特点是反复发烧和发冷、贫血（红细胞丢失）以及重要器官受损，如果不及时治疗，可能会在症状出现后数小时内致命。直到最近，非洲的治疗仍依赖于氯喹和磺胺多辛-乙胺嘧啶。不幸的是，对这两种抗疟药物产生抗药性的寄生虫现在很普遍。因此，世界卫生组织目前推荐青蒿素联合疗法用于治疗非洲和其他耐药性疟疾常见地区的恶性疟。在这种疗法中，青蒿素衍生物（新型速效抗疟药）与另一种抗疟药联合使用，以减少恶性疟原虫对任一药物产生耐药性的机会。 恶性疟原虫通过获得“抗性突变”而对抗疟药物产生抗药性，“抗性突变”是阻止这些药物杀死寄生虫的基因变化。编码氯喹抗性转运蛋白的基因中的突变会导致对氯喹的抗性，二氢叶酸还原酶基因中的一组特定突变会导致对乙胺嘧啶的抗性，编码二氢蝶酸合酶的基因 dhps 中的几个突变与磺胺多辛的抗性相关。科学家发现，导致氯喹和乙胺嘧啶耐药的突变起源于亚洲，并分别于 20 世纪 70 年代末和 20 世纪 80 年代中期传播到非洲（可能多次）。这些源自亚洲的突变现在在整个非洲都很常见，因此无法确定它们是如何在整个非洲大陆传播的。然而，此类信息将有助于专家设计有效措施来控制耐药性恶性疟原虫的传播。由于引起磺胺多辛耐药性的 dhps 突变在 20 世纪 90 年代中期才开始出现，因此尚未在非洲均匀传播。因此，在这项研究中，研究人员使用遗传方法来描述非洲 dhps 抗性突变的地理起源和当代分布。研究人员分析了从非洲各国疟疾患者采集的血液样本中恶性疟原虫 DNA 的 dhps 突变，并在科学文献中搜索了其他类似的研究。这些数据共同表明，目前非洲存在五种主要的 dhps 序列变体（其中三种包含突变，在实验室测试中赋予磺胺多辛不同程度的抗性），每种序列都有独特的地理分布。特别是，数据显示东非和西非的恶性疟原虫携带不同的耐药突变。接下来，研究人员在 dhps 基因侧翼的 DNA 中寻找微卫星变异。微卫星是含有短的、重复的核苷酸序列的DNA区域。由于重复次数可能会有所不同，并且微卫星与附近的基因一起遗传，因此可以通过检查不同突变体 dhps 基因侧翼的微卫星来确定各种抗性突变的祖先。该分析揭示了五个区域集群，其中在该区域内检查的所有地点都存在相同的抗性谱系，并且还表明东非和西非的抗性突变具有不同的祖先。这些发现表明，磺胺多辛抗药性恶性疟原虫最近在非洲多个地点独立出现，并且东非和西非磺胺多辛抗药性的分子基础不同。后一个结果可能具有临床意义，因为它表明磺胺多辛作为抗疟药的有效性在整个非洲大陆可能有所不同。最后，尽管需要分析更多样本才能全面了解抗疟疾耐药性在非洲的传播情况，但这些发现表明，经济和交通基础设施可能通过影响人类迁徙，在控制最近寄生虫在非洲大陆的传播方面发挥了作用。因此，在非洲社会经济相关地区开展协调一致的疟疾控制运动可能比仅限于国家领土的运动更有效地减轻非洲疟疾负担。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.1000055。 Tim Anderson 的 PLoS Medicine Perspective 进一步讨论了这项研究 MedlinePlus 百科全书包含有关疟疾的页面（英语和西班牙语） 世界卫生组织提供有关疟疾（多种语言）和耐药性疟疾的信息 美国疾病控制和预防中心提供有关疟疾的信息（英语和西班牙语） 遏制疟疾合作伙伴关系提供有关其全球控制疟疾的方法以及世界特定地区的疟疾控制工作的信息 WorldWide抗疟药耐药性网络正在创建一个有关抗疟药耐药性的国际数据库
Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa. Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. Resistant dhps has emerged independently in multiple sites in Africa during the past 10–20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns. Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year, mostly in sub-Saharan Africa. People become infected with P. falciparum when they are bitten by a mosquito that has acquired the parasite in a blood meal taken from an infected person. P. falciparum malaria, which is characterized by recurring fevers and chills, anemia (loss of red blood cells), and damage to vital organs, can be fatal within hours of symptom onset if untreated. Until recently, treatment in Africa relied on chloroquine and sulfadoxine–pyrimethamine. Unfortunately, parasites resistant to both these antimalarial drugs is now widespread. Consequently, the World Health Organization currently recommends artemisinin combination therapy for the treatment of P. falciparum malaria in Africa and other places where drug-resistant malaria is common. In this therapy, artemisinin derivatives (new fast-acting antimalarial agents) are used in combination with another antimalarial to reduce the chances of P. falciparum becoming resistant to either drug. P. falciparum becomes resistant to antimalarial drugs by acquiring “resistance mutations,” genetic changes that prevent these drugs from killing the parasite. A mutation in the gene encoding a protein called the chloroquine resistance transporter causes resistance to chloroquine, a specific group of mutations in the dihydrofolate reductase gene causes resistance to pyrimethamine, and several mutations in dhps, the gene that encodes dihydropteroate synthase, are associated with resistance to sulfadoxine. Scientists have discovered that the mutations causing chloroquine and pyrimethamine resistance originated in Asia and spread into Africa (probably multiple times) in the late 1970s and mid-1980s, respectively. These Asian-derived mutations are now common throughout Africa and, consequently, it is not possible to determine how they spread across the continent. Information of this sort would, however, help experts design effective measures to control the spread of drug-resistant P. falciparum. Because the mutations in dhps that cause sulfadoxine resistance only began to emerge in the mid-1990s, they haven't spread evenly across Africa yet. In this study, therefore, the researchers use genetic methods to characterize the geographical origins and contemporary distribution of dhps resistance mutations in Africa. The researchers analyzed dhps mutations in P. falciparum DNA from blood samples collected from patients with malaria in various African countries and searched the scientific literature for other similar studies. Together, these data show that five major variant dhps sequences (three of which contain mutations that confer various degrees of resistance to sulphadoxine in laboratory tests) are currently present in Africa, each with a unique geographical distribution. In particular, the data show that P. falciparum parasites in east and west Africa carry different resistance mutations. Next, the researchers looked for microsatellite variants in the DNA flanking the dhps gene. Microsatellites are DNA regions that contain short, repeated sequences of nucleotides. Because the number of repeats can vary and because microsatellites are inherited together with nearby genes, the ancestry of various resistance mutations can be worked out by examining the microsatellites flanking different mutant dhps genes. This analysis revealed five regional clusters in which the same resistance lineage was present at all the sites examined within the region and also showed that the resistance mutations in east and west Africa have a different ancestry. These findings show that sulfadoxine-resistant P. falciparum has recently emerged independently at multiple sites in Africa and that the molecular basis for sulfadoxine resistance is different in east and west Africa. This latter result may have clinical implications because it suggests that the effectiveness of sulfadoxine as an antimalarial drug may vary across the continent. Finally, although many more samples need to be analyzed to build a complete picture of the spread of antimalarial resistance across Africa, these findings suggest that economic and transport infrastructures may have played a role in governing recent parasite dispersal across this continent by affecting human migration. Thus, coordinated malaria control campaigns across socioeconomically linked areas in Africa may reduce the African malaria burden more effectively than campaigns that are confined to national territories. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000055. This study is further discussed in a PLoS Medicine Perspective by Tim Anderson The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish) Information is available from the World Health Organization on malaria (in several languages) and on drug-resistant malaria The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish) Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria, and on malaria control efforts in specific parts of the world The WorldWide Antimalarial Resistance Network is creating an international database about antimalarial drug resistance
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