Quantifying the removal of red blood cells in Macaca mulatta during a Plasmodium coatneyi infection
Quantifying the removal of red blood cells in Macaca mulatta during a Plasmodium coatneyi infection
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DOI：
10.1186/s12936-016-1465-5
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发表时间：
2016-08-12
期刊：
影响因子：
3
通讯作者：
Voit, Eberhard O.
中科院分区：
文献类型：
--
作者：
Fonseca, Luis L.;Alezi, Harnel S.;Voit, Eberhard O.
背景：疟疾是全球人类最致命的寄生虫病，与疟疾的长期共存在人类基因组中留下了不可磨灭的印记，导致多种遗传性疾病。尽管贫血是疟疾常见的临床并发症，但疟疾贫血发病机制的根本原因和机制尚不清楚，也很难在人类中进行研究。非人灵长类 (NHP) 模型系统能够对疟疾贫血的潜在致病因素，特别是严重贫血的发生进行机制研究和量化。 方法：数据是在疟原虫和半免疫恒河猴 (Macaca mulatta) 感染科特尼疟原虫的过程中获得的，这些猕猴的红细胞 (RBC) 在感染时用生物素进行了原位标记。感染开始了。这些数据用于生存分析，首次能够准确估计猕猴红细胞的寿命。这些数据还为红细胞周转递归动态模型的开发和参数化奠定了基础，该模型用于量化每只猕猴红细胞的产生和清除。结果：计算分析表明，猕猴红细胞的寿命为 98 +/- 21 天。该模型还明确表明，衰老和寄生虫血症导致的死亡不足以解释感染引起的贫血的程度。具体来说，该模型首次允许量化红细胞死亡的不同原因，即正常衰老、与年龄无关的随机损失、寄生和未感染细胞的旁观者效应。仅靠实验手段很难对整个红细胞去除过程进行这样的剖析。在未感染疟疾的猕猴中，正常生理衰老过程造成的红细胞死亡占 20%，而寄生仅占 4%，而旁观者效应与红细胞总损失的惊人比例相关，高达 76%。对涉及旁观者效应的替代机制进行的基于模型的比较表明，大部分损失可能是由于清除所有年龄段的未感染红细胞的过程造成的，并且只有极少数是由于未感染红细胞衰老率增加所致。结论：开发了一种新的疟疾血液阶段模型，用于分析穆拉塔疟原虫感染的数据特征。该模型使用具有年龄结构的离散递归框架，可以量化红细胞去除的最重要的病理生理过程。计算结果显示，这种寄生虫引起的疟疾贫血主要是由于与年龄无关的过程导致未感染红细胞的损失。该过程的生物学特性和完整机制尚未完全了解，需要进一步研究。
Background: Malaria is the most deadly parasitic disease in humans globally, and the long-time coexistence with malaria has left indelible marks in the human genome that are the causes of a variety of genetic disorders. Although anaemia is a common clinical complication of malaria, the root causes and mechanisms involved in the pathogenesis of malarial anaemia are unclear and difficult to study in humans. Non-human primate (NHP) model systems enable the mechanistic study and quantification of underlying causative factors of malarial anaemia, and particularly the onset of severe anaemia.Methods: Data were obtained in the course of Plasmodium coatneyi infections of malaria-naive and semi-immune rhesus macaques (Macaca mulatta), whose red blood cells (RBCs) were labelled in situ with biotin at the time the infections were initiated. The data were used for a survival analysis that permitted, for the first time, an accurate estimation of the lifespan of erythrocytes in macaques. The data furthermore formed the basis for the development and parameterization of a recursive dynamic model of erythrocyte turnover, which was used for the quantification of RBC production and removal in each macaque.Results: The computational analysis demonstrated that the lifespan of erythrocytes in macaques is 98 +/- 21 days. The model also unambiguously showed that death due to senescence and parasitaemia is not sufficient to account for the extent of infection-induced anaemia. Specifically, the model permits, for the first time, the quantification of the different causes of RBC death, namely, normal senescence, age-independent random loss, parasitization, and bystander effects in uninfected cells. Such a dissection of the overall RBC removal process is hardly possible with experimental means alone. In the infected malaria-naive macaques, death of erythrocytes by normal physiological senescence processes accounts for 20 % and parasitization for only 4 %, whereas bystander effects are associated with an astonishing 76 % of total RBC losses. Model-based comparisons of alternative mechanisms involved in the bystander effect revealed that most of the losses are likely due to a process of removing uninfected RBCs of all age classes and only minimally due to an increased rate of senescence of the uninfected RBCs.Conclusions: A new malaria blood-stage model was developed for the analysis of data characterizing P. coatneyi infections of M. mulatta. The model used a discrete and recursive framework with age-structure that allowed the quantification of the most significant pathophysiological processes of RBC removal. The computational results revealed that the malarial anaemia caused by this parasite is mostly due to a loss of uninfected RBCs by an age-independent process. The biological identity and complete mechanism of this process is not fully understood and requires further investigation.