pc4covid19/COVID19: Version 0.5.0: draft v5 prototype

COVID19 tissue simulator

Version: 0.5.0

Release date: 19 October 2021

• An improved systemic immune model (v0.2.0) that adds B-Cells, Plasma Cells, and Ig including time delays to simulate transport.
• ROS induced apoptosis; neutrophils secrete ROS on phagocytosis.
• fibroblast and anti-inflammatory cytokine changes.
• Antibodies (Ig) in the tissue.
• CD8+ and CD4+ T Cell tissue phenotype changes.
• More macrophage states.

This model simulates replication 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 iteratively prototyped and refined with community support (see below).

This multiscale simulator combines several model components:

• Tissue: Virus, cell debris, interferons, immunoglobulin (antibodies), and chemokines diffuse within the extracellular space. They may also "decay" to reflect removal by interstitial flow into nearby blood vessels or airways. In version 0.5.0, Virus and immunoglobulin react for Virus removal in the tissue.
• 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 induced death. Infected cells also secrete Type-I interferon which induces the inhibition of viral protein synthesis. Dead cells release some or all of their internal contents, notably including virions.
• Pyroptosis death model: 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: Fibroblast-mediated collagen deposition 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: 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, CD8+T cells and immunoglobulin. Time delays can be defined to account for Cell Travel time of DCs, CD8+ and CD4+ 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. In version 0.5.0, neutrophils secrete reative oxygen species (ROS) upon phagocytosis, which can cause ROS induced apoptosis.
  • CD8+T cells are recruited by the lymph node. 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 tothem.
  • CD4+T cells are recruited by the lymph node. 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 cytokines secreted by CD4+T cells.
  • Dendritic cells residentially exist in the tissue and are activated by infected cells and/or virus. A 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 in the location where infected cells are killed by CD8+T cells for a set time.
  • immunoglobulin is produced in the lymph node and sent to the tissue. They bind and remove Virion in the tissue and bind to infected cells for macrophage removal. ### 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.

make : compiles the project.

make clean : removes all .o files and the executable, so that the next "make" recompiles the entire project

make data-cleanup : clears out all simulation data

make reset : reset to default settings (restores config file)

Preprint: https://doi.org/10.1101/2020.04.02.019075

Model details: https://github.com/MathCancer/COVID19/wiki/About

Homepage: http://covid19.PhysiCell.org

Support: https://sourceforge.net/p/physicell/tickets/

Latest info: follow @PhysiCell and @MathCancer on Twitter (http://twitter.com/MathCancer)

See changes.md for the full change log.