LAPSE:2020.0994
Published Article
LAPSE:2020.0994
Mathematical Modeling of RNA Virus Sensing Pathways Reveals Paracrine Signaling as the Primary Factor Regulating Excessive Cytokine Production
Jordan J. A. Weaver, Jason E. Shoemaker
September 23, 2020
RNA viruses, such as influenza and Severe Acute Respiratory Syndrome (SARS), invoke excessive immune responses; however, the kinetics that regulate inflammatory responses within infected cells remain unresolved. Here, we develop a mathematical model of the RNA virus sensing pathways, to determine the intracellular events that primarily regulate interferon, an important protein for the activation and management of inflammation. Within the ordinary differential equation (ODE) model, we incorporate viral replication, cell death, interferon stimulated genes’ antagonistic effects on viral replication, and virus sensor protein (TLR and RIG-I) kinetics. The model is parameterized to influenza infection data using Markov chain Monte Carlo and then validated against infection data from an NS1 knockout strain of influenza, demonstrating that RIG-I antagonism significantly alters cytokine signaling trajectory. Global sensitivity analysis suggests that paracrine signaling is responsible for the majority of cytokine production, suggesting that rapid cytokine production may be best managed by influencing extracellular cytokine levels. As most of the model kinetics are host cell specific and not virus specific, the model presented provides an important step to modeling the intracellular immune dynamics of many RNA viruses, including the viruses responsible for SARS, Middle East Respiratory Syndrome (MERS), and Coronavirus Disease (COVID-19).
Keywords
cytokine storm, interferon signaling, ODE modeling, systems biology
Subject
Suggested Citation
Weaver JJA, Shoemaker JE. Mathematical Modeling of RNA Virus Sensing Pathways Reveals Paracrine Signaling as the Primary Factor Regulating Excessive Cytokine Production. (2020). LAPSE:2020.0994
Author Affiliations
Weaver JJA: Department of Chemical & Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15260, USA
Shoemaker JE: Department of Chemical & Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15260, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Computational and Systems Biology, Univers [ORCID]
Journal Name
Processes
Volume
8
Issue
6
Article Number
E719
Year
2020
Publication Date
2020-06-20
Published Version
ISSN
2227-9717
Version Comments
Original Submission
Other Meta
PII: pr8060719, Publication Type: Journal Article
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LAPSE:2020.0994
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doi:10.3390/pr8060719
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Sep 23, 2020
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CC BY 4.0
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Sep 23, 2020
 
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Sep 23, 2020
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https://psecommunity.org/LAPSE:2020.0994
 
Original Submitter
Calvin Tsay
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