Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission.
Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission.
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DOI：
10.7554/elife.04692
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发表时间：
2014-11-18
期刊：
影响因子：
7.7
通讯作者：
Ghani AC
中科院分区：
文献类型：
--
作者：
White MT;Karl S;Battle KE;Hay SI;Mueller I;Ghani AC
间日疟原虫复发感染发生在潜伏的肝期寄生虫（催眠虫）激活后，在初次感染后几周到几个月引起新的血期感染。我们开发了肝脏期催眠子的宿主内数学模型，并对间日疟原虫热带菌株的数据进行了验证。宿主内模型嵌入到间日疟原虫传播模型中，以证明在新感染后催眠子岩库的建立以及通过催眠子岩的激活和死亡而耗尽。据预测，催眠子石储层将过度分散，许多个体只有很少的催眠子石或没有催眠子石，有些人的肝脏受到严重感染。具有更多催眠子的个体预计会经历更多的复发，并对间日疟原虫的传播做出更多贡献。将催眠虫杀灭药物如伯氨喹纳入一线治疗方案，预计将大大减少间日疟原虫的传播，因为拥有最多催眠虫的个体更有可能复发并成为治疗的目标。DOI: http://dx.doi.org/10.7554/eLife.04692.001疟疾是世界上最致命的传染病之一，尽管它既可预防又可治愈，但每年仍有成千上万的人死于疟疾。疟疾是由疟原虫引起的，它通过蚊子在人与人之间传播。当蚊子叮咬人类时，疟原虫通过蚊子的唾液被注射到血液中。然后寄生虫通过血液传播到肝脏，感染肝细胞并在这些细胞内繁殖，而不会引起任何明显的症状。在肝脏中沉默了几周或几个月后，现在大量存在的寄生虫破坏了宿主的肝细胞，重新进入血液，并开始感染红细胞。如果另一只蚊子叮咬了受感染的个体并吸食了血液，寄生虫就会进入蚊子体内，传播循环继续下去。已知有几种疟原虫可引起疟疾。研究最广泛的物种是恶性疟原虫，它也是最致命的疟疾之一。然而，另一种被称为间日疟原虫的疟原虫是分布最广泛的疟原虫，尽管它的毒性不如恶性疟原虫，但它特别危险，因为它会引起反复发作的疟疾。与恶性疟原虫相比，间日疟原虫有能力形成催眠虫：一种休眠形式的寄生虫，可以在肝细胞内停留很长一段时间，有时长达数年。间日疟原虫催眠虫的储存库可以有规律地以寄生虫的传染性形式填充血液，引发疟疾的复发。即使复发的患者及时接受治疗以清除血液中的寄生虫，更多的寄生虫可能会从肝脏中出现并引起新的血期感染。White等人开发了一个数学模型来帮助理解间日疟原虫是如何传播的。与许多已建立的疟疾传播模型不同，新模型解释了肝脏中间日疟原虫催眠虫的储存库，并假设储存库中的催眠虫要么死亡，要么被激活并以恒定的速率进入血液。这产生的模式与患者复发的频率密切匹配。White等人继续预测，尽管许多感染者的肝脏中很少或没有催眠虫，但有些人有很多催眠虫，这些人更容易患疟疾复发。这表明，如果对疟疾患者的初始治疗中加入额外的药物来杀死肝脏中的催眠虫，那么就有可能大大减少间日疟原虫的传播程度。DOI: http://dx.doi.org/10.7554/eLife.04692.002
Plasmodium vivax relapse infections occur following activation of latent liver-stages parasites (hypnozoites) causing new blood-stage infections weeks to months after the initial infection. We develop a within-host mathematical model of liver-stage hypnozoites, and validate it against data from tropical strains of P. vivax. The within-host model is embedded in a P. vivax transmission model to demonstrate the build-up of the hypnozoite reservoir following new infections and its depletion through hypnozoite activation and death. The hypnozoite reservoir is predicted to be over-dispersed with many individuals having few or no hypnozoites, and some having intensely infected livers. Individuals with more hypnozoites are predicted to experience more relapses and contribute more to onwards P. vivax transmission. Incorporating hypnozoite killing drugs such as primaquine into first-line treatment regimens is predicted to cause substantial reductions in P. vivax transmission as individuals with the most hypnozoites are more likely to relapse and be targeted for treatment. DOI: http://dx.doi.org/10.7554/eLife.04692.001 Malaria is one of the world's most deadly infections, causing 100s of 1000s of deaths each year despite being both preventable and curable. Malaria is caused by Plasmodium parasites, which are transmitted between humans by mosquitoes. When a mosquito bites a human, Plasmodium is injected into the bloodstream with the mosquito's saliva. The parasite then travels through the bloodstream to the liver, infects liver cells and multiplies within those cells without causing any noticeable symptoms. After remaining silent in the liver for weeks or months, the now abundant parasite ruptures the host liver cell, re-enters the bloodstream, and begins infecting red blood cells. If another mosquito bites the infected individual and takes a blood meal, the parasite moves into the mosquito and the cycle of transmission continues. There are several species of Plasmodium that are known to cause malaria. The most widely studied species is P. falciparum, which also causes one of the deadliest types of malaria. However, another Plasmodium species called P. vivax is the most widely distributed species and, despite being less virulent than P. falciparum, is particularly dangerous because it causes recurring malaria. In contrast to P. falciparum, P. vivax has the ability to form hypnozoites: a dormant form of the parasite that can remain inside liver cells for long periods of time, sometimes for years. The reservoir of P. vivax hypnozoites can regularly populate the bloodstream with the infectious form of the parasite, triggering relapses of malaria. Even if an individual suffering a relapse receives prompt treatment to clear parasites in the blood, more parasites may emerge from the liver and cause new blood-stage infections. White et al. developed a mathematical model to help understand how P. vivax is transmitted. Unlike many of the established models of malaria transmission, the new model accounts for the reservoir of P. vivax hypnozoites in the liver, and assumes that hypnozoites in the reservoir either die, or are activated and enter the bloodstream, at a constant rate. This produces patterns that closely match how often relapses occur in patients. White et al. go on to predict that although many infected people have few or no hypnozoites in their liver, some have many hypnozoites, and these people are more likely to suffer from malaria relapses. This suggests that if the initial treatments given to malaria sufferers incorporate additional drugs that kill the hypnozoites in the liver, then it may be possible to substantially reduce the extent of P. vivax transmission. DOI: http://dx.doi.org/10.7554/eLife.04692.002