Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus.
Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus.
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DOI：
10.1186/s12918-016-0345-5
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发表时间：
2016-10-22
影响因子：
--
通讯作者：
Ait-Ali T
中科院分区：
文献类型：
--
作者：
Doeschl-Wilson A;Wilson A;Nielsen J;Nauwynck H;Archibald A;Ait-Ali T
巨噬细胞对于针对许多病原体的先天免疫是必不可少的，但一些病原体也靶向巨噬细胞作为感染途径。猪繁殖与呼吸综合征病毒（Porcine Reproductive and Respiratory Syndrome virus，PRRSV）是一种感染猪肺泡巨噬细胞（PAM）的RNA病毒，对全球养猪业造成毁灭性影响。确定介导PAM对病毒易感性的细胞机制对于开发有效的干预措施至关重要。先前的证据表明，清道夫受体CD 163是生产性感染的PAM与PRRSV是必不可少的。在这里，我们使用一个综合的体外模拟方法来确定PAM对PRRSV的易感性是否以及如何随时间变化，以评估CD 163表达对这种变化的作用，并推断改变细胞易感性的其他潜在致病机制。我们的体外实验表明，PAM对PRRSV的敏感性随着孵育时间的推移而发生显著变化。此外，越来越多的比例的PAM明显缺乏CD 163被发现在后期的孵育阶段对PRRSV易感，因此与目前的理解，即CD 163是生产性感染的PAM与PRRSV是必不可少的。我们开发了基于过程的动态数学模型，并将这些模型与数据拟合，以评估关于观察到的易感性和生物标志物趋势的潜在潜在机制的替代假设。我们的数据所告知的模型支持这样的假设，即虽然CD 163可能增强了细胞易感性，但在我们的研究中，它对生产性感染并不是必需的。相反，该模型促进可逆细胞状态的存在，如巨噬细胞极化，由自分泌因子以密度依赖性方式介导，负责观察到的细胞易感性动力学。我们的动态模型推理方法提供了强有力的支持，PAM对PRRS病毒的易感性是短暂的，可逆的，并且可以由靶细胞本身产生的化合物介导，并且这些可以使缺乏CD 163受体的PAM对PRRSV易感。这些结果对开发旨在增强靶细胞抗性的治疗方法具有意义，并促进未来对巨噬细胞对PRRSV和其他病毒易感性动态变化的研究。本文的在线版本（doi：10.1186/s12918-016-0345-5）包含补充材料，可供授权用户使用。
Macrophages are essential to innate immunity against many pathogens, but some pathogens also target macrophages as routes to infection. The Porcine Reproductive and Respiratory Syndrome virus (PRRSV) is an RNA virus that infects porcine alveolar macrophages (PAMs) causing devastating impact on global pig production. Identifying the cellular mechanisms that mediate PAM susceptibility to the virus is crucial for developing effective interventions. Previous evidence suggests that the scavenger receptor CD163 is essential for productive infection of PAMs with PRRSV. Here we use an integrative in-vitro–in-silico modelling approach to determine whether and how PAM susceptibility to PRRSV changes over time, to assess the role of CD163 expression on such changes, and to infer other potential causative mechanisms altering cell susceptibility. Our in-vitro experiment showed that PAM susceptibility to PRRSV changed considerably over incubation time. Moreover, an increasing proportion of PAMs apparently lacking CD163 were found susceptible to PRRSV at the later incubation stages, thus conflicting with current understanding that CD163 is essential for productive infection of PAMs with PRRSV. We developed process based dynamic mathematical models and fitted these to the data to assess alternative hypotheses regarding potential underlying mechanisms for the observed susceptibility and biomarker trends. The models informed by our data support the hypothesis that although CD163 may have enhanced cell susceptibility, it was not essential for productive infection in our study. Instead the models promote the existence of a reversible cellular state, such as macrophage polarization, mediated in a density dependent manner by autocrine factors, to be responsible for the observed kinetics in cell susceptibility. Our dynamic model–inference approach provides strong support that PAM susceptibility to the PRRS virus is transient, reversible and can be mediated by compounds produced by the target cells themselves, and that these can render PAMs lacking the CD163 receptor susceptible to PRRSV. The results have implications for the development of therapeutics aiming to boost target cell resistance and prompt future investigation of dynamic changes in macrophage susceptibility to PRRSV and other viruses. The online version of this article (doi:10.1186/s12918-016-0345-5) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Go N;Bidot C;Belloc C;Touzeau S
通讯作者：
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通讯作者：
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