Simulating coxsackievirus B3 infection with an accessible computational model of its complete kinetics

Figures

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  Figure 1. MacOS folder setup for MATLAB runtime For the CVB3 model to run correctly on MacOS, MATLAB Runtime must be installed in the MATLAB folder within the Applications directory. The v910 folder within “MATLAB Runtime” is set up automatically when installing MATLAB Runtime.

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  Figure 2. Demonstration of a single simulation and sequential simulations (A) The graphical output is the result of running the model with default settings. (B) The graphical output of a second simulation (blue) using MOI 5 is overlaid on the first simulation (red). The blue box highlights changes made for the simulation. The solid lines show the median number of virions over time, and the dotted lines show the upper (95%) and lower (5%) quantiles.

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  Figure 3. Turning off the antiviral response and plotting a different species The graphical output is the result of running a third simulation (green) after the simulations shown in Figure 2 (red and blue). The third simulation was run at an MOI of 5 with the cellular antiviral response turned off. (A) Virion production increases without an antiviral response. (B) No interferon stimulated proteins are produced when the antiviral response is turned off. The green box highlights changes made for the simulation. The solid lines show the median number of virions over time, and the dotted lines show the upper (95%) and lower (5%) quantiles.

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  Figure 4. Adding exogenous IFN stimulation The graphical output is the result of running a fourth simulation (cyan) after the simulation shown in Figure 3. The fourth simulation was run at an MOI of 5 with exogenous IFN stimulation starting at 6 h post infection and the host antiviral response on. The plot shows total positive-sense single-stranded RNA (+ssRNA) on a logscale y-axis with the quantile lines turned off. The cyan boxes highlight changes made for the simulation. The solid lines show the median number of virions over time.

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  Figure 5. A simulation in population mode The graphical output is the result of running a simulation in Population mode instead of Single Cell mode. In Population mode, the number of viral particles in each run is randomly selected from a Poisson distribution with the mean set at the input MOI. The plot shows the mean (dotted line) and the median (solid line) virions over time.

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  Figure 6. Performing a single-parameter sensitivity analysis The graphical output is the result of running a sensitivity analysis for positive-strand RNA concentration at 16 h post infection. On the x-axis are parameters that were individually scaled up or down by the indicated multiplication factor on the y-axis relative to the base parameter set. The Hill constant was varied multiplicatively below one and additively above one, where 2 = base Hill coefficient + 1. Orange rectangles indicate parameter values that increased positive-strand RNA concentration compared to default, whereas blue rectangles indicate decreased positive-strand RNA concentration. The sensitivity analysis plot was processed in Adobe Illustrator.

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  Figure 7. Model GUI outputs for the selected species during a viral life cycle The simulation was performed for 6 h with all other parameters set to their default values. (A and B) Species from the delivery module decrease early in the viral life cycle. The concentration of Endosomal +ssRNA (B) is low due to the transient nature of the species. (C–F) Species from the replication module increase over the course of viral infection. Once VROs are formed (C, arrow), the number of translation complexes rapidly increases (D), which causes an explosive increase in viral proteins (E) that can then replicate the viral genome (F). (G–I) Species from the encapsidation module appear in a time-dependent manner. Early RNA–pentamer species (G) appear before intermediate RNA–pentamer species (H), which appear earlier than filled virions (I). +ssRNA: positive-sense single-stranded viral RNA. VRO: viral replication organelle. +ssRNA-nxPentamer: one +ssRNA bound to n associated pentamers. The simulations were run in the CVB3 model GUI, and the plots were collected using the Export Plot button then processed in Adobe Illustrator. The solid lines show the median number of virions over time, and the dotted…

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  Figure 8. Model GUI outputs for selected species identify a threshold viral polymerase rate for productive infection Four simulations were performed with iterative threefold decreases in the viral polymerase rate (180–6.67 kb/h). All other simulation parameters were set to default. (A) Viral entry—measured by endosomal positive-sense single-strand viral RNA (+ssRNA)—is unaffected by the viral polymerase rate. The concentration of Endosomal +ssRNA is low due to the transient nature of the species. (B and C) Species in the replication module are sensitive to the viral polymerase rate. The decrease in Total +ssRNA (B) decreases the amount of available template for translation of viral proteins (C). (D) A threshold viral polymerase rate for productive infection. No virion production is observed for the lowest viral polymerase rate (6.67 kb/h), presumably due to the lack of +ssRNA (B) and capsid protein (C). The simulations were run in the CVB3 model GUI, and the plots were collected using the Export Plot button then processed in Adobe Illustrator. The solid lines show the median number of virions over time, and the dotted lines show the upper (95%) and lower (5%) quantiles.

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  Figure 9. Model GUI outputs comparing single cell mode to population mode at a low MOI The simulation was performed for 16 h with MOI set at 2 in either Single Cell mode (A) or Population mode (B) with all other parameters set to their default values. (A) At a low MOI, a single cell does not yield a productive infection (solid blue). (B) In a population of cells, the median response is the same as in a single cell (solid red), while the mean virion production of the entire population yields a quantifiable response (dotted red). The simulations were run in the CVB3 model GUI, and the plots were collected using the Export Plot button then processed in Adobe Illustrator.

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  Figure 10. Model GUI outputs comparing serial simulations with different run counts All other parameters were set to their default values. (A) Five simulations with Number of runs set to 10. (B) Five simulations with Number of runs set to 100. The simulations were run in the CVB3 model GUI, and the plots were collected using the Export Plot button then processed in Adobe Illustrator. The solid lines show the median number of virions over time, and the dotted lines show the upper (95%) and lower (5%) quantiles.