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bioRxiv · 10.1101/2020.07.26.222174

Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback

Lopacinski, A. B.·Sweatt, A. J.·Smolko, C. M.·Gray-Gaillard, E.·Borgmann, C. A.·Shah, M.·Janes, K. A.
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Abstract

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 kinetics are built from detailed modules for 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 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.

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Lopacinski, A. B., Sweatt, A. J., Smolko, C. M., Gray-Gaillard, E., Borgmann, C. A., Shah, M., Janes, K. A.. 2020-07-26. Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback. https://doi.org/10.1101/2020.07.26.222174

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