Estimating biologically relevant parameters under uncertainty for experimental within-host murine West Nile virus infection
Estimating biologically relevant parameters under uncertainty for experimental within-host murine West Nile virus infection
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DOI：
10.1098/rsif.2016.0130
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发表时间：
2016-04-01
影响因子：
3.9
通讯作者：
Perelson, Alan S.
中科院分区：
文献类型：
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作者：
Banerjee, Soumya;Guedj, Jeremie;Perelson, Alan S.
西尼罗河病毒（WNV）是一种新出现的病原体，它已使鸟类大量灭绝，并在人类中引起严重的病毒性脑炎暴发。目前，人们对西尼罗河病毒在感染过程中的宿主内病毒动力学知之甚少。我们建立了数学模型来描述野生型和免疫功能低下小鼠的病毒复制、传播和宿主免疫反应。我们的方法将靶细胞限制模型与免疫功能受损敲除小鼠的病毒血症数据相匹配，并将适应性免疫反应模型与野生型小鼠的数据相匹配。使用这种方法，我们首先使用没有免疫反应的简单模型估计控制病毒产生和病毒在宿主中的传播的参数。然后，我们在一个更复杂的免疫反应模型中使用这些参数来表征体液免疫反应的动力学。尽管输入参数存在很大的不确定性，但我们的分析对由模型参数的非线性组合组成的重要病毒特征产生了相对精确的估计：我们估计宿主内基本繁殖数R-0的平均值为2.3（95%的值在1.7-2.9范围内）；传染性病毒粒子爆发的平均大小为2.9个斑块形成单位（95%的值在1.7-4.7之间）；每个感染病毒粒子平均感染的细胞数在0.3到0.99之间。我们的分析提供了对西尼罗河病毒感染动力学的机制见解，并产生了难以通过实验测量的病毒特征的估计。这些模型是定量了解体液免疫反应减少宿主病毒血症的时间和有效性的第一步，从而减少了西尼罗河病毒的流行传播。
West Nile virus (WNV) is an emerging pathogen that has decimated bird populations and caused severe outbreaks of viral encephalitis in humans. Currently, little is known about the within-host viral kinetics of WNV during infection. We developed mathematical models to describe viral replication, spread and host immune response in wild-type and immunocompromised mice. Our approach fits a target cell-limited model to viremia data from immunocompromised knockout mice and an adaptive immune response model to data from wild-type mice. Using this approach, we first estimate parameters governing viral production and viral spread in the host using simple models without immune responses. We then use these parameters in a more complex immune response model to characterize the dynamics of the humoral immune response. Despite substantial uncertainty in input parameters, our analysis generates relatively precise estimates of important viral characteristics that are composed of nonlinear combinations of model parameters: we estimate the mean within-host basic reproductive number, R-0, to be 2.3 (95% of values in the range 1.7-2.9); the mean infectious virion burst size to be 2.9 plaque-forming units (95% of values in the range 1.7-4.7); and the average number of cells infected per infectious virion to be between 0.3 and 0.99. Our analysis gives mechanistic insights into the dynamics of WNV infection and produces estimates of viral characteristics that are difficult to measure experimentally. These models are a first step towards a quantitative understanding of the timing and effectiveness of the humoral immune response in reducing host viremia and consequently the epidemic spread of WNV.