Biophysics Group, Department of Physics, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
Genomics and Evolutionary Medicine Unit (GEM), Center of Excellence in Malaria Research, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Sci Rep. 2020 Apr 10;10(1):6219. doi: 10.1038/s41598-020-63283-2.
Resistance to antimalarial drugs is currently a growing public health problem, resulting in more cases with treatment failure. Although previous studies suggested that a concentration gradient facilitates the antibiotic resistance evolution in bacteria, no attempt has been made to investigate the roles of a concentration gradient in malaria drug resistance. Unlike the person-to-person mode of transmission of bacteria, the malaria parasites need to switch back and forth between the human and mosquito hosts to complete the life cycle and to spread the resistant alleles. Here we developed a stochastic combined within- and between-hosts evolutionary dynamics model specific to malaria parasites in order to investigate the influence of an antimalarial concentration gradient on the evolutionary dynamics of malaria drug resistance. Every stage of malaria development in both human and mosquito hosts are individually modelled using the tau-leaping algorithm. We found that the concentration gradient can accelerate antimalarial resistance evolution. The gain in resistance evolution was improved by the increase in the parasite mutation rate and the mosquito biting rate. In addition, even though the rate of resistance evolution is not sensitive to the changes in parasite reduction ratios (PRRs) of antimalarial drugs, the probability of finding the antimalarial drug resistant parasites decreases when the PRR increases.
抗疟药物耐药性目前是一个日益严重的公共卫生问题，导致更多的治疗失败病例。尽管先前的研究表明浓度梯度有助于促进细菌对抗生素的耐药性进化，但尚未有人尝试研究浓度梯度在疟疾药物耐药性中的作用。与细菌的人际传播模式不同，疟原虫需要在人和蚊子宿主之间来回切换才能完成生命周期并传播耐药等位基因。在这里，我们开发了一种针对疟疾寄生虫的随机组合的宿主内和宿主间进化动力学模型，以研究抗疟药物浓度梯度对疟疾药物耐药性进化动力学的影响。使用 tau-跳跃算法分别对人类和蚊子宿主中的疟疾发展的每个阶段进行建模。我们发现浓度梯度可以加速抗疟药物耐药性的进化。寄生虫突变率和蚊子叮咬率的增加提高了耐药性的进化收益。此外，尽管抗疟药物的寄生虫减少率（PRR）变化对抗疟药物耐药性进化的速率不敏感，但当 PRR 增加时，发现抗疟药物耐药性寄生虫的概率会降低。
