Multicellular Spatial Model of RNA Virus Replication and Interferon Responses Reveals Factors Controlling Plaque Growth Dynamics

Abstract Respiratory viruses present major health challenges, as evidenced by the 2009 influenza pandemic and the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Severe RNA virus respiratory infections often correlate with high viral load and excessive inflammation. Un...

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Bibliographic Details
Published in:bioRxiv 2021-03
Main Authors: Aponte-Serrano, Josua O, Weaver, Jordan Ja, Sego, Tj, Glazier, James A, Shoemaker, Jason E
Format: Article
Language:English
Subjects:
Antiviral agents
Bronchopulmonary infection
Cell culture
Computer applications
Coronaviruses
COVID-19
Cytokine storm
Cytokines
Diffusion
Drug development
Epithelial cells
Experiments
Immune response
Immune system
Immunosuppressive agents
Infections
Inflammation
Influenza
Innate immunity
Interferon
Lungs
Pandemics
Phosphorylation
Plaques
Replication
RNA viruses
Sensitivity analysis
Severe acute respiratory syndrome coronavirus 2
Signal transduction
Systems Biology
Viruses
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Summary:Abstract Respiratory viruses present major health challenges, as evidenced by the 2009 influenza pandemic and the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Severe RNA virus respiratory infections often correlate with high viral load and excessive inflammation. Understanding the dynamics of the innate immune response and its manifestation at the cell and tissue levels are vital to understanding the mechanisms of immunopathology and developing improved, strain independent treatments. Here, we present a novel spatialized multicellular spatial computational model of two principal components of tissue infection and response: RNA virus replication and type-I interferon mediated antiviral response to infection within lung epithelial cells. The model is parameterized using data from influenza virus infected cell cultures and, consistent with experimental observations, exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. Modulating the phosphorylation of STAT or altering the ratio of the diffusion constants of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of arrest on diffusion constants highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro experiments to measure these diffusion constants. Sensitivity analyses were performed under conditions creating both continuous plaque growth and arrested plaque growth. Findings suggest that plaque growth and cytokine assay measurements should be collected during arrested plaque growth, as the model parameters are significantly more sensitive and more likely to be identifiable. The model’s metrics replicate experimental immunostaining imaging and titer based sampling assays. The model is easy to extend to include SARS-CoV-2-specific mechanisms as they are discovered or to include as a component linking epithelial cell signaling to systemic immune models. Author Summary COVID-19 is possibly the defining healthcare crisis of the current generation, with tens of millions of global cases and more than a million reported deaths. Respiratory lung infections form lesions in the lungs, whose number and size correlate with severity of illness. In some severe cases, the disease triggers a severe inflammatory condition known as cytokine storm. Given the complexity of the immune system, computational modeling is ne
ISSN:2692-8205
DOI:10.1101/2021.03.16.435618