对柯萨奇病毒 B3 的完整动力学进行建模揭示了宿主细胞反馈的人类决定因素。
Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback.
机构信息
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21231, USA.
出版信息
Cell Syst. 2021 Apr 21;12(4):304-323.e13. doi: 10.1016/j.cels.2021.02.004. Epub 2021 Mar 18.
Complete kinetic models are pervasive in chemistry but lacking in biological systems. We encoded the complete kinetics of infection for coxsackievirus B3 (CVB3), a compact and fast-acting RNA virus. The model consists of separable, detailed modules describing viral binding-delivery, translation-replication, and encapsidation. Specific module activities are dampened by the type I interferon response to viral double-stranded RNAs (dsRNAs), which is itself disrupted by viral proteinases. The experimentally validated kinetics uncovered that cleavability of the dsRNA transducer mitochondrial antiviral signaling protein (MAVS) becomes a stronger determinant of viral outcomes when cells receive supplemental interferon after infection. Cleavability is naturally altered in humans by a common MAVS polymorphism, which removes a proteinase-targeted site but paradoxically elevates CVB3 infectivity. These observations are reconciled with a simple nonlinear model of MAVS regulation. Modeling complete kinetics is an attainable goal for small, rapidly infecting viruses and perhaps viral pathogens more broadly. A record of this paper's transparent peer review process is included in the Supplemental information.
完整的动力学模型在化学中很普遍，但在生物系统中却缺乏。我们为柯萨奇病毒 B3（CVB3）编码了完整的感染动力学，这是一种紧凑且快速作用的 RNA 病毒。该模型由可分离的详细模块组成，分别描述病毒的结合-传递、翻译-复制和包裹过程。I 型干扰素对病毒双链 RNA（dsRNA）的反应会抑制特定模块的活性，而病毒蛋白酶本身也会破坏这种反应。经过实验验证的动力学揭示，当细胞在感染后补充干扰素时，dsRNA 转导物线粒体抗病毒信号蛋白（MAVS）的切割能力成为决定病毒结果的一个更强的决定因素。人类中常见的 MAVS 多态性会自然改变 MAVS 的切割能力，虽然这种多态性去除了一个蛋白酶靶向位点，但却出人意料地提高了 CVB3 的感染性。这些观察结果与 MAVS 调节的简单非线性模型相一致。对于小型、快速感染的病毒，以及更广泛的病毒病原体，实现完整动力学建模是一个可行的目标。本文的透明同行评审过程记录包含在补充信息中。
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