The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332-2000, USA.
Malaria Host-Pathogen Interaction Center, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30322, USA.
Malar J. 2018 Nov 6;17(1):410. doi: 10.1186/s12936-018-2560-6.
Malaria is a major mosquito transmitted, blood-borne parasitic disease that afflicts humans. The disease causes anaemia and other clinical complications, which can lead to death. Plasmodium vivax is known for its reticulocyte host cell specificity, but many gaps in disease details remain. Much less is known about the closely related species, Plasmodium cynomolgi, although it is naturally acquired and causes zoonotic malaria. Here, a computational model is developed based on longitudinal analyses of P. cynomolgi infections in nonhuman primates to investigate the erythrocyte dynamics that is pertinent to understanding both P. cynomolgi and P. vivax malaria in humans.
A cohort of five P. cynomolgi infected Rhesus macaques (Macaca mulatta) is studied, with individuals exhibiting a plethora of clinical outcomes, including varying levels of anaemia. A discrete recursive model with age structure is developed to replicate the dynamics of P. cynomolgi blood-stage infections. The model allows for parasitic reticulocyte preference and assumes an age preference among the mature RBCs. RBC senescence is modelled using a hazard function, according to which RBCs have a mean lifespan of 98 ± 21 days.
Based on in vivo data from three cohorts of macaques, the computational model is used to characterize the reticulocyte lifespan in circulation as 24 ± 5 h (n = 15) and the rate of RBC production as 2727 ± 209 cells/h/µL (n = 15). Analysis of the host responses reveals a pre-patency increase in the number of reticulocytes. It also allows the quantification of RBC removal through the bystander effect.
The evident pre-patency increase in reticulocytes is due to a shift towards the release of younger reticulocytes, which could result from a parasite-induced factor meant to increase reticulocyte availability and satisfy the parasite's tropism, which has an average value of 32:1 in this cohort. The number of RBCs lost due to the bystander effect relative to infection-induced RBC losses is 62% for P. cynomolgi infections, which is substantially lower than the value of 95% previously determined for another simian species, Plasmodium coatneyi.
疟疾是一种主要由蚊子传播的血液寄生虫病，会感染人类。这种疾病会导致贫血和其他临床并发症，严重时可能导致死亡。已知间日疟原虫（Plasmodium vivax）对网织红细胞具有宿主细胞特异性，但关于该疾病的许多细节仍不清楚。尽管间日疟原虫的近亲恶性疟原虫（Plasmodium cynomolgi）也是自然感染的，并引起人畜共患疟疾，但对其了解甚少。在这里，我们基于对非人类灵长类动物感染恶性疟原虫的纵向分析，建立了一个计算模型，以研究与理解人类恶性疟原虫和间日疟原虫疟疾相关的红细胞动力学。
我们对五只感染恶性疟原虫的恒河猴（Macaca mulatta）进行了研究，这些个体表现出多种临床结局，包括不同程度的贫血。我们建立了一个具有年龄结构的离散递归模型来复制恶性疟原虫血期感染的动力学。该模型允许寄生虫对网织红细胞的偏好，并假设成熟红细胞之间存在年龄偏好。根据红细胞衰老的危险函数模型，红细胞的平均寿命为 98±21 天。
根据来自三个恒河猴队列的体内数据，我们使用计算模型来描述循环中网织红细胞的寿命为 24±5 小时（n=15），红细胞生成率为 2727±209 个细胞/小时/微升（n=15）。对宿主反应的分析表明，潜伏期前网织红细胞数量增加。它还可以量化通过旁观者效应导致的红细胞清除。
潜伏期前网织红细胞的明显增加是由于年轻网织红细胞的释放增加，这可能是寄生虫诱导的因素所致，旨在增加网织红细胞的可用性并满足寄生虫的嗜性，在本队列中，平均嗜性为 32:1。由于旁观者效应导致的红细胞丢失与感染诱导的红细胞丢失的比例为 62%，对于恶性疟原虫感染来说，这一比例显著低于先前确定的另一种灵长类动物疟原虫（Plasmodium coatneyi）的 95%。
