Study on antimalarial efficacy and genetic diversities of human, parasites and mosquitoes

人类寄生虫和疟疾寄生虫在不同地理区域以不同频率表现出的遗传多样性是制定疟疾控制战略（包括疟疾化疗和疟疾疫苗）的主要障碍。我们调查了瓦努阿图不同疟疾流行岛屿上的一些遗传多样性。瓦努阿图的疟疾不稳定，主要是低流行到中流行和季节性，偶尔流行。瓦努阿图的细胞色素P450 (CYP) 2C 19突变等位基因频率一致较高。然而，不同岛屿的人口之间存在差异。遗传、语言和地理模式的比较表明，短距离基因流动是瓦努阿图目前CYP2C19等位基因分布的主要原因。我们在疟疾患者中的数据表明，CYP2C19突变与原胍向环胍（一种强二氢叶酸还原酶（DHFR）抑制剂）代谢不良之间存在关联，并且存在明显的剂量效应关系。在瓦努阿图4个孤岛上的140例恶性疟原虫病例中发现了dhfr基因有限的多样性。所有分离株均有相同的Asn-108突变，除gaa中的3株外，所有分离株均有Arg-59突变，通常与dhfr抑制药物的中等耐药有关。gaa剩余的3个分离株具有His-51，这是以前文献中未报道的变化。尽管存在这些部分耐药变异，乙胺嘧啶和磺胺多辛治疗仍然非常有效。瓦努阿图岛屿不稳定疟疾流行中dhfr基因多样性有限，至少部分原因可能是由于岛屿间基因流动有限的周期性传播中断和隔离导致寄生虫种群杂合性丧失。人的GYP2C19和寄生虫的dhfr基因突变分别与原胍代谢不良和对环胍耐药有关，这两种基因突变都被认为与原胍抗疟效果差有关。然而，我们观察到proguanil在cyp2c19相关的低代谢基因型和常见的dhfr基因型（Arg-59和Asn-108）患者中也有很高的抗疟效果。这表明母体化合物原胍具有独立于代谢物环胍和dhfr突变的内在功效。通过将大量药物管理与浸渍蚊帐和食饵鱼相结合，我们很可能已经在地方性不稳定的Aneityum岛上阻断了疟疾的传播，并取得了持续和重大的成果。过去9年的定期脾脏和血液调查显示，除了两例输入性感染（1993年一例混合感染和1999年一例间日疟原虫感染）外，自1996年以来，在MDA和间日疟原虫之后，完全没有出现恶性疟原虫。这表明，如果在整个传播地区进行干预，并且在社区同意和参与的框架内控制疟疾输入的风险，就可以消除疟疾。少

The genetic diversities displayed by human and malaria parasites at different frequencies in different geographical areas represent a major obstacle for the development of malaria control strategies including malaria chemotherapy and malaria vaccine. We investigated some genetic diversities on Vanuatu islands with various malaria endemicities. Malaria in Vanuatu is unstable, mainly hypo to mesoendemic and seasonal with occasional epidemics.The frequencies of the cytochrome P450 (CYP) 2C 19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19 alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent ge … More ne dose effect relationship.Restricted diversity in the dhfr gene was shown in a total of 140 P. falciparum cases on 4 isolated islands of Vanuatu. All isolates had the same Asn-108 mutation, and all, except 3 in Gaua, also had Arg-59 mutation, normally associated with moderate resistance toDHFR-inhibiting drugs. The 3 remaining isolates in Gaua had His-51, a change not previously reported in the literature. Despite these partly resistant variants, pyrimethamine and sulfadoxine treatment was still highly effective. The restricted diversity of the dhfr gene in unstable malaria endemicity on Vanuatu islands maybe at least partly explained by a loss in heterozygosity of the parasite populations derived from periodically interrupted transmission and isolation with limited gene flows between islands.Mutations in human GYP2C19 and parasite dhfr genes, related to poor metabolism of proguanil and resistance to cycloguanil respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. We however observed high antimalarial efficacy of proguanil also in patients with CYP2C19-reIated poor metabolizer genotype and the common dhfr genotype (Arg-59 and Asn-108). This suggested that the parent compound proguanil has an intrinsic efficacy independent of the metabolite cycloguanil and the dhfr mutation.By combining mass drug administration with impregnated bed nets and larvivorous fish, we have most probably interrupted malaria transmission on Aneityum island with unstable endemicity and achieved sustained and significant gains. Periodicspleen and blood surveys for the past nine years have showed complete absence of Plasmodium falciparum after the MDA and P vivax from 1996 onwards, with the exception of two instances of imported infections (one mixed infection in 1993 and one P. vivax infection in 1999), suggesting that malaria can be eliminated if the intervention is conducted over the whole area of transmission and the risk of importation of malaria is controlled within a framework of community consent and participation. Less