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bioRxiv · 10.1101/2021.03.16.435618

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

Aponte-Serrano, J. O.·Weaver, J. J. A.·Sego, T. J.·Glazier, J. A.·Shoemaker, J. E.
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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 models 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 SummaryCOVID-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 needed to link molecular signaling at the site of inflection to the signaling impact on the overall immune system, ultimately revealing how severe inflammatory conditions may emerge. Here, we created a computational model of the early stages of infection that simulates lung cells infected with RNA viruses, such those responsible for COVID-19 and influenza, to help explore how the disease forms viral plaques, an in vitro analog to lesion growth in the lung. Our model recapitulates in vitro observations that pretreatment of biological signaling molecules called with type-I interferons, which are currently being evaluated for treatment of COVID-19. Analyzing the model, we, can stop viral plaque growth. We found that enhancing certain aspects of the innate immune system, such as the JAK/STAT pathway, may be able to stop viral plaque growth, suggesting molecules involved in this pathway as possible drug candidates. Quantifying the parameters needed to model interferon signaling and viral replication, experiments should be performed under conditions that inhibit viral growth, such as pretreating cells with interferon. We present a computational framework that is essential to constructing larger models of respiratory infection induced immune responses, can be used to evaluate drugs and other medical interventions quickly, cheaply, and without the need for animal testing during the initial phase, and that defines experiments needed to improve our fundamental understanding of the mechanisms regulating the immune response.

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Aponte-Serrano, J. O., Weaver, J. J. A., Sego, T. J., Glazier, J. A., Shoemaker, J. E.. 2021-03-16. Multicellular Spatial Model of RNA Virus Replication and Interferon Responses Reveals Factors Controlling Plaque Growth Dynamics. https://doi.org/10.1101/2021.03.16.435618

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