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

Aaron B. Lopacinski, Andrew J. Sweatt, Christian M. Smolko, Elise Gray-Gaillard, Cheryl A. Borgman, Millie Shah, View ORCID ProfileKevin A. Janes
doi: https://doi.org/10.1101/2020.07.26.222174
Aaron B. Lopacinski
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
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Andrew J. Sweatt
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
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Christian M. Smolko
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
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Elise Gray-Gaillard
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
2Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
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Cheryl A. Borgman
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
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Millie Shah
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
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  • For correspondence: ms2kf@virginia.edu kjanes@virginia.edu
Kevin A. Janes
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
3Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA
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  • ORCID record for Kevin A. Janes
  • For correspondence: ms2kf@virginia.edu kjanes@virginia.edu
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SUMMARY

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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵5 Lead Contact

  • The version includes revised main and supplementary figures that address reviewer comments.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 23, 2021.
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Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback
Aaron B. Lopacinski, Andrew J. Sweatt, Christian M. Smolko, Elise Gray-Gaillard, Cheryl A. Borgman, Millie Shah, Kevin A. Janes
bioRxiv 2020.07.26.222174; doi: https://doi.org/10.1101/2020.07.26.222174
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Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback
Aaron B. Lopacinski, Andrew J. Sweatt, Christian M. Smolko, Elise Gray-Gaillard, Cheryl A. Borgman, Millie Shah, Kevin A. Janes
bioRxiv 2020.07.26.222174; doi: https://doi.org/10.1101/2020.07.26.222174

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