A modular framework for multiscale, multicellular, spatiotemporal modeling of acute primary viral infection and immune response in epithelial tissues and its application to drug therapy timing and effectiveness
Fig 2
(A) Model objects, processes and interactions: Conceptual model of an epithelial tissue and lymph node. Schematic representation of the model objects, processes and interactions. Epithelial and immune cells refer to the two main classes of cells. Interactions occur within an extracellular environment, and a compartmental model of a lymph node controls immune-cell recruitment to the tissue. Together the epithelial-cell, extracellular-environment and immune-cell components represent the epithelial tissue. Each model object has associated processes that dictate its states and behaviors. Epithelial-cell processes include viral internalization (E1), viral replication (E2), viral release (E3) and cell death (E4). Immune cell processes include activation (I1), chemotaxis (I2), contact cytotoxicity (I3) and oxidative cytotoxicity (I4). Activated immune cells participate in oxidative cytotoxicity (I4) and secrete oxidative agents into the oxidizing-agent field (T3). Activated cells become inactive after 1 hour. The virus field (T1), cytokine field (T2) and oxidizing-agent field (T3) describe spatially-varying densities of extracellular components. Field processes describe diffusive transport and clearance of material in the extracellular environment and activated transport to the lymph nodes. The lymph node is a single-compartment model whose pro- or anti-inflammatory state specifies the recruitment or removal rate (L1) of immune cells in the epithelial tissue. The transport of cytokines to the lymph node promotes its proinflammatory state. (B) Viral Life Cycle: Interactions in the viral internalisation, replication and release models. Schematic representation of inputs, outputs and interactions between stages of the viral replication model. Extracellular viral particles (represented as continuous fields) are internalized by the viral internalization model and initiate the viral replication model. The main stages of the viral replication model are: unpacking, viral genome replication, protein synthesis and viral assembly and packaging. The output of the viral replication model passes to the viral release model, which transfers newly assembled viral particles from the cells into the extracellular environment. (C) Cell types and transitions. Epithelial cells are of type uninfected if they have not yet internalized any virus (E1). They are of type infected if they have internalized virus, but are not releasing virus into the virus field (viral release E3 is inactive). They are of type virus releasing if they are releasing virus into the extracellular virus field (i.e., viral release E3 is activated). Immune cells are initially inactive and do not participate in the oxidative cytotoxicity (I4) or chemotax towards higher concentrations of the cytokine field (I2). They become activated when they experience activation (I1). In all panels, dashed arrows with barbed heads represent transformations, solid arrows with barbed heads represent transport and solid arrows with lollipop heads represent regulation.