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Abstract
COVID19 tissue simulator
This model simulates viral dynamics of SARS-CoV-2 (coronavirus / COVID19) in a layer of epithelium and several submodels (such as single-cell response, pyroptosis death model, tissue-damage model, lymph node model and immune response). It is being rapidly prototyped and refined with community support (see below).
Please note that this is a stochastic model: for some simulation runs, you may see the immune system fail to respond. Users are encouraged to try the simulation multiple times.
This multiscale simulator combines several model components:
- Tissue: Virus, cell debris, and chemokines diffuse within the extracellular space. They may also “decay” to reflect removal by interstitial flow into nearby blood vessels or airways.
- ACE2 receptor dynamics: Virions bind to ACE2 receptors on the surface, which are internalized (endocytosed) into cells. After virions are released from internalized receptors, they can return to the surface.
- Viral replication: Internalized virus is uncoated to expose viral RNA, which synthesizes viral proteins that are assembled into virions. Assembled virions are transported to the cell surface to be exported to the tissue (exocytosed).
- Single-cell response: Infected cells secrete a chemokine that may attract immune cells. In a simple pharmacodynamics response (to assembled virions), infected cells can undergo apoptosis. In version 4, infected cells also secrete Type-I interferon which induces the inhibition of viral protein synthesis. Apoptosed cells release some or all of their internal contents, notably including virions.
- Pyroptosis death model: In version 4, we introduced a model of cell death via pyroptosis. Viral RNA levels within the cell act as a DAMP/PAMP that initiates the pyroptosis cascade. The intracellular processes result in the secretion of cytokines IL-1β and IL-18, as well as cell swelling and rupture.
- Tissue-damage model: In version 4, fibroblast-mediated collagen deposition was included to account for the fibrosis at the damaged site in response to immune response-induced tissue injury, in which fibroblast cells are recruited into the tissue by following the gradient of anti-inflammatory cytokine and deposit collagen in the place where infected cells are killed by CD8+ T cells.
- Lymph node (LN) model: In version 4, the external immune system was incorporated in the whole model. The presence of virus and infected cells in the tissue induces dendritic cells to activate and egress out of tissue to lymph nodes, where they present antigen to induce activation and proliferation of virus-specific CD4+ T cells and CD8+ T cells.
- Immune response:
- Resident (and recruited) macrophages seek apoptotic cells. They phagocytose (ingest) dead cells upon contact and activate. They also break down ("digest") ingested materials.
- Activated macrophages release a pro-inflammatory cytokine to recruit other immune cells, while seeking both apoptotic and infected cells by chemotaxis. Activated macrophages can “wear out” and apoptose after phagocytosing too much material.
- Exhausted macrophages are active macrophages that internalised debris is above a threshold. They would stop phagocytosing in this stage.
- Hyperactivated macrophages are able to phagocytose infected cells with at least one intracellular viral protein when CD4+ T cells induce macrophages to a hyperactive state.
- Neutrophils are recruited by accumulated pro-inflammatory cytokine. They seek apoptotic cells, phagocytose them, and activate. Activated neutrophils seek both apoptotic and infected cells. Neutrophils also capture extracellular virions.
- CD8+ T cells are recruited by accumulated pro-inflammatory cytokine. They seek and adhere to infected cells. After sufficient contact time with one or more CD8+ T cells, infected cells undergo apoptosis. They would increase proliferation rate and killing efficacy after activated DCs present antigen to them.
- CD4+ T cells are recruited by accumulated pro-inflammatory cytokine. They apoptose naturally and become dead cells. They are activated in the lymph node by three signals: (1) antigenic presentation by the DCs, (2) direct activation by cytokines secreted by DCs, (3) direct activation by cyto-kines secreted by CD4+ T cells.
- Dendritic cells residential exit in the tissue and are activated by infected cells and/or virus. Portion of activated DCs leave the tissue to travel to the lymph node. Activated DCs present antigen to CD8+ T cells, which benefits them from improving proliferation rate and killing efficacy.
- Fibroblast are recruited into the tissue by anti-inflammatory cytokine. Fibroblast cells apoptose naturally and become dead cells. They move locally in the tissue along up gradients of anti-inflammatory cytokine and deposit collagen continuously in the location where infected cells are killed by CD8+ T cells.
Please cite this project via the preprint:
M. Getz et al., Rapid community-driven development of a SARS-CoV-2 tissue simulator. bioRxiv 2020.04.02.019075, 2020, (Preprint). doi: 10.1101/2020.04.02.019075.
Legend:
- lung epithelium: are colored by their (assembled) virion loads in four colors
- . Cells with 0 assembled virions.
- . Cells with 1-9 assembled virions.
- . Cells with 10-99 assembled virions.
- . Cells with 100-999 assembled virions.
- . Cells with 1000+ assembled virions.
- . Apoptotic (dead from viral load)
- CD8+ T cells: are colored by their cell cycle status
- . G0G1, S, G2, M cycle
- . Apoptotic
- CD4+ T cells: are colored by their cell cycle status
- . G0G1, S, G2, M cycle
- . Apoptotic
- macrophage: are colored by their cell cycle status
- . G0G1, S, G2, M cycle
- . Activated macrophage
- . Exhausted macrophage
- . Hyperactivated macrophage
- . Apoptotic
- neutrophil: are colored by their cell cycle status
- . G0G1, S, G2, M cycle
- . Apoptotic
- fibroblast: are colored by their cell cycle status
- . G0G1, S, G2, M cycle
- . Apoptotic
- Dendritic cells: are colored by their cell cycle status
- . G0G1, S, G2, M cycle
- . Activated DC
- . Apoptotic
- Background: Contour plot of released virus that is diffusing in and above the tissue.
Caveats and disclaimers
This model is under active development using rapid prototyping:
- It has not been peer reviewed.
- It is intended to drive basic scientific research and public education at this stage.
- It cannot be used for public policy decisions.
- It cannot be used for individual medical decisions.
This model will be continually refined with input from the community, particularly experts in infectious diseases. The validation state will be updated as this progresses.
GUI Overview
- Config Basics tab: input parameters common to all models (e.g., domain grid, simulation time, choice/frequency of outputs)
- Microenvironment tab: microenvironment parameters that are model-specific
- User Params tab: user parameters that are model-specific
- Cell Types tab: parameters for cell types that are model-specific
- Out: Plots tab: output display of cells and substrates
Clicking the 'Run' button will use the specified parameters and start a simulation. When clicked, it creates an "Output" widget that can be clicked/expanded to reveal the progress of the simulation. When the simulation generates output files, they can be visualized in the "Out: Plots" tab. The "# cell frames" will be dynamically updated as those output files are generated by the running simulation. When the "Run" button is clicked, it toggles to a "Cancel" button that will terminate (not pause) the simulation.
Model details
This model is being rapidly prototyped. Biological and mathematical detail can be found at:
- Project website: http://covid19.physicell.org (opens in new tab)
- Model feedback: Google feedback form (opens in new tab)
- Preprint: Getz et al. (2020) (opens in new tab)
- GitHub codes: pc4covid19 GitHub organization (opens in new tab)
We request community help in estimating parameters and improving model assumptions at the link above.
This model and cloud-hosted demo are part of the education and outreach for the IU Engineered nanoBIO Node and the NCI-funded cancer systems biology grant U01CA232137. The models are built using PhysiCell: a C++ framework for multicellular systems biology.
Basic instructions
Modify parameters in the "Config Basics", "Microenvironment", "User Params", or "Cell Types" tabs. Click the "Run" button once you are ready.
To view the output results, click the "Out: Plots" tab, and move the slider bar to advance through simulation frames. Note that as the simulation runs, the "# cell frames" field will increase, so you can view more simulation frames.
If there are multiple substrates defined in the Microenvironment, you can select a different one from the drop-down widget in the Plots tab. You can also fix the colormap range of values.
Note that you can download full simulation data for further exploration in your tools of choice.
About the software:
This model and cloud-hosted demo are part of the education and outreach for the IU Engineered nanoBIO Node and the NCI-funded cancer systems biology grant U01CA232137. The models are built using PhysiCell: a C++ framework for multicellular systems biology [1] for the core simulation engine and xml2jupyter [2] to create the graphical user interface (GUI).
- A. Ghaffarizadeh, R. Heiland, S.H. Friedman, S.M. Mumenthaler, and P. Macklin. PhysiCell: an open source physics-based cell simulator for 3-D multicellular systems. PLoS Comput. Biol. 14(2):e1005991, 2018. DOI: 10.1371/journal.pcbi.1005991.
- R. Heiland, D. Mishler, T. Zhang, E. Bower, and P. Macklin. xml2jupyter: Mapping parameters between XML and Jupyter widgets. Journal of Open Source Software 4(39):1408, 2019. DOI: 10.21105/joss.01408.
Powered by
This software is powered by PhysiCell [1-2], a powerful simulation tool that combines multi-substrate diffusive transport and off-lattice cell models. PhysiCell is BSD-licensed, and available at:
- GitHub releases: https://github.com/MathCancer/PhysiCell/releases
- SourceForge downloads: https://sourceforge.net/projects/physicell/
It is a C++, cross-platform code with minimal software dependencies. It has been tested and deployed in Linux, BSD, OSX, Windows, and other environments, using the standard g++ compiler.
See http://PhysiCell.MathCancer.org.
The Jupyter-based GUI was auto-generated by xml2jupyter [3], a technique to create graphical user interfaces for command-line scientific applications.
References
[1] Ghaffarizadeh A, Heiland R, Friedman SH, Mumenthaler SM, Macklin P (2018) PhysiCell: An open source physics-based cell simulator for 3-D multicellular systems. PLoS Comput Biol 14(2): e1005991. https://dx.doi.org/10.1371/journal.pcbi.1005991
[2] Ghaffarizadeh A, Friedman SH, Macklin P (2016) BioFVM: an efficient, parallelized diffusive transport solver for 3-D biological simulations. Bioinformatics 32(8):1256-8. https://dx.doi.org/10.1093/bioinformatics/btv730
[3] Heiland R, Mishler D, Zhang T, Bower E, Macklin P (2019) Xml2jupyter: Mapping parameters between XML and Jupyter widgets. J Open Source Software 4(39):1408. https://dx.doi.org/10.21105/joss.01408
[4] Ozik J, Collier N, Wozniak J, Macal C, Cockrell C, Friedman S, Ghaffarizadeh A, Heiland R, An G, Macklin P (2018). High-throughput cancer hypothesis testing with an integrated PhysiCell-EMEWS workflow. BMC Bioinformatics 19:483. https://dx.doi.org/10.1186/s12859-018-2510-x.
[5] Ozik J, Collier N, Heiland R, An G, and Macklin P (2019). Learning-accelerated discovery of immune-tumor interactions. Molec. Syst. Design Eng. 4:747-60. https://dx.doi.org/10.1039/c9me00036d
Cite this work
Researchers should cite this work as follows:
-
Please cite:
M. Getz et al (2020) Rapid community-driven development of a SARS-CoV-2 tissue simulator. bioRxiv preprint 2020.04.02.019075. https://doi.org/10.1101/2020.04.02.019075