Understanding and Predicting Strain-Specific Patterns of Pathogenesis in the Rodent Malaria Plasmodium chabaudi
Understanding and Predicting Strain-Specific Patterns of Pathogenesis in the Rodent Malaria Plasmodium chabaudi
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DOI：
10.1086/591684
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发表时间：
2008-11-01
影响因子：
2.9
通讯作者：
Day, Troy
中科院分区：
文献类型：
--
作者：
Mideo, Nicole;Barclay, Victoria C.;Day, Troy
尽管相当成功地阐明了重要的免疫和资源为基础的机制，控制感染的动力学在一些疾病，很少有人知道这些机制的差异如何导致菌株的发病机制的模式差异。使用数据和理论的结合，我们解开生态因素的作用（例如，资源丰富）在CD4（+）T细胞耗竭小鼠中疟疾种夏氏疟原虫发病机制的动力学中的作用。我们建立了一系列嵌套模型，系统地测试了一些潜在的监管机制，并使用统计技术确定“最佳”模型。最佳拟合模型进一步测试使用一个独立的数据集从混合克隆竞争实验。我们发现，寄生虫优先侵入老年人的红细胞，即使他们是更肥沃的年轻的网织红细胞和接种量有很强的影响，爆发网织红细胞的大小。重要的是，结果表明，菌株特异性的毒力差异来自红细胞年龄特异性侵入率和爆发大小的差异，因为这些对于毒性较低的菌株较低，以及来自每种菌株诱导的造血水平的差异。我们的分析强调了模型选择和验证对于揭示新的生物学见解的重要性。
Despite considerable success elucidating important immunological and resource-based mechanisms that control the dynamics of infection in some diseases, little is known about how differences in these mechanisms result in strain differences in patterns of pathogenesis. Using a combination of data and theory, we disentangle the role of ecological factors (e.g., resource abundance) in the dynamics of pathogenesis for the malaria species Plasmodium chabaudi in CD4(+) T cell-depleted mice. We build a series of nested models to systematically test a number of potential regulatory mechanisms and determine the "best" model using statistical techniques. The best-fit model is further tested using an independent data set from mixed-clone competition experiments. We find that parasites preferentially invade older red blood cells even when they are more fecund in younger reticulocytes and that inoculum size has a strong effect on burst size in reticulocytes. Importantly, the results suggest that strain-specific differences in virulence arise from differences in red blood cell age-specific invasion rates and burst sizes, since these are lower for the less virulent strain, as well as from differences in levels of erythopoesis induced by each strain. Our analyses highlight the importance of model selection and validation for revealing new biological insights.