Search

Respiratory viruses present major public health challenges, as evidenced by the 1918 Spanish Flu, the 1957 H2N2, 1968 H3N2, and 2009 H1N1 influenza pandemics, 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 manifestations at the cell and tissue levels is vital to understanding the mechanisms of immunopathology and to developing strain-independent treatments. Here, we present a novel spatialized multicellular computational model of RNA virus infection and the type-I interferon-mediated antiviral response that it induces within lung epithelial cells. The model is built using the CompuCell3D multicellular simulation environment and is parameterized using data from influenza virus-infected cell cultures. Consistent with experimental observations, it exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. The model suggests that modifying the activity of signaling molecules in the JAK/STAT pathway or altering the ratio of the diffusion lengths of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of plaque growth arrest on diffusion lengths highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro measurement of these diffusion coefficients. Sensitivity analyses under conditions leading to continuous or arrested plaque growth found that plaque growth is more sensitive to variations of most parameters and more likely to have identifiable model parameters when conditions lead to plaque arrest. This result suggests that cytokine assay measurements may be most informative under conditions leading to arrested plaque growth. The model is easy to extend to include SARS-CoV-2-specific mechanisms or to use as a component in models linking epithelial cell signaling to systemic immune models., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JAG is the owner/operator of Virtual Tissues for Health, LLC, which develops applications of multiscale tissue models in medical applications and is a shareholder in Gilead Life Sciences.

Background: The biophysics of an organism span multiple scales from subcellular to organismal and include processes characterized by spatial properties, such as the diffusion of molecules, cell migration, and flow of intravenous fluids. Mathematical biology seeks to explain biophysical processes in mathematical terms at, and across, all relevant spatial and temporal scales, through the generation of representative models. While non-spatial, ordinary differential equation (ODE) models are often used and readily calibrated to experimental data, they do not explicitly represent the spatial and stochastic features of a biological system, limiting their insights and applications. However, spatial models describing biological systems with spatial information are mathematically complex and computationally expensive, which limits the ability to calibrate and deploy them and highlights the need for simpler methods able to model the spatial features of biological systems., Results: In this work, we develop a formal method for deriving cell-based, spatial, multicellular models from ODE models of population dynamics in biological systems, and vice versa. We provide examples of generating spatiotemporal, multicellular models from ODE models of viral infection and immune response. In these models, the determinants of agreement of spatial and non-spatial models are the degree of spatial heterogeneity in viral production and rates of extracellular viral diffusion and decay. We show how ODE model parameters can implicitly represent spatial parameters, and cell-based spatial models can generate uncertain predictions through sensitivity to stochastic cellular events, which is not a feature of ODE models. Using our method, we can test ODE models in a multicellular, spatial context and translate information to and from non-spatial and spatial models, which help to employ spatiotemporal multicellular models using calibrated ODE model parameters. We additionally investigate objects and processes implicitly represented by ODE model terms and parameters and improve the reproducibility of spatial, stochastic models., Conclusion: We developed and demonstrate a method for generating spatiotemporal, multicellular models from non-spatial population dynamics models of multicellular systems. We envision employing our method to generate new ODE model terms from spatiotemporal and multicellular models, recast popular ODE models on a cellular basis, and generate better models for critical applications where spatial and stochastic features affect outcomes., (© 2021. The Author(s).)

Simulations of tissue-specific effects of primary acute viral infections like COVID-19 are essential for understanding disease outcomes and optimizing therapies. Such simulations need to support continuous updating in response to rapid advances in understanding of infection mechanisms, and parallel development of components by multiple groups. We present an open-source platform for multiscale spatiotemporal simulation of an epithelial tissue, viral infection, cellular immune response and tissue damage, specifically designed to be modular and extensible to support continuous updating and parallel development. The base simulation of a simplified patch of epithelial tissue and immune response exhibits distinct patterns of infection dynamics from widespread infection, to recurrence, to clearance. Slower viral internalization and faster immune-cell recruitment slow infection and promote containment. Because antiviral drugs can have side effects and show reduced clinical effectiveness when given later during infection, we studied the effects on progression of treatment potency and time-of-first treatment after infection. In simulations, even a low potency therapy with a drug which reduces the replication rate of viral RNA greatly decreases the total tissue damage and virus burden when given near the beginning of infection. Many combinations of dosage and treatment time lead to stochastic outcomes, with some simulation replicas showing clearance or control (treatment success), while others show rapid infection of all epithelial cells (treatment failure). Thus, while a high potency therapy usually is less effective when given later, treatments at late times are occasionally effective. We illustrate how to extend the platform to model specific virus types (e.g., hepatitis C) and add additional cellular mechanisms (tissue recovery and variable cell susceptibility to infection), using our software modules and publicly-available software repository., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JAG is the owner/operator of Virtual Tissues for Health, LLC, which develops applications of multiscale tissue models in medical applications and is a shareholder in Gilead Life Sciences.