Institut de Biologie Computationnelle (IBC), 34095, Montpellier, France.
Institut de Recherche en Cancérologie de Montpellier, Institut régional du Cancer Montpellier & Université de Montpellier, IRCM-INSERM U1194, 34298, Montpellier, France.
Malar J. 2017 Dec 19;16(1):493. doi: 10.1186/s12936-017-2140-1.
Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008-2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs.
Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population.
Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations.
恶性疟原虫疟疾是人类最广泛的寄生虫感染之一，仍然是全球主要的健康关注问题。青蒿素联合疗法是治疗疟疾的一线药物，但其耐药性的出现和传播威胁着消除疟疾的努力。已经确定了与青蒿素药物耐药性相关的有前途的分子标记和途径，但耐药性的潜在分子机制仍不清楚。评估了青蒿素耐药性早期出现（2008-2011 年）的基因组数据，目的是通过使用 21257 个 SNP 面板对 167 个寄生虫分离株进行特征描述，来确定柬埔寨青蒿素耐药性起源地与 k13 相关的遗传背景。
鉴定出了 8 个子群体，这表明存在一个与青蒿素耐药性获得一致的过程，符合出现-选择-扩散模型，并得到了动态平衡理论的支持。鉴定出种群特异性突变有助于鉴定与青蒿素耐药性和相关途径相关的核心集合 57 个背景基因。分析表明，青蒿素耐药性的背景不是在药物压力后获得的，而是由于固定后对来自祖先种群的子群体进行选择的结果。
青蒿素耐药性亚群的功能分析说明了泛素化和细胞分裂或分化之间的强烈相互作用在青蒿素耐药寄生虫中。这些途径与 P. falciparum 耐药亚群以及除 k13 之外的耐药标记物的关系，突出了混合寄生虫群体在青蒿素耐药背景扩散中的主要作用。在选择后，耐药基因在柬埔寨混合人群中的扩散是由于敏感和耐药寄生虫群体的配子体交配所致。
