Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.

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 correlat...

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Autores principales:	Josua O Aponte-Serrano, Jordan J A Weaver, T J Sego, James A Glazier, Jason E Shoemaker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/665229f699cf4d378040ea345b385a8a
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spelling	oai:doaj.org-article:665229f699cf4d378040ea345b385a8a2021-12-02T19:58:12ZMulticellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.1553-734X1553-735810.1371/journal.pcbi.1008874https://doaj.org/article/665229f699cf4d378040ea345b385a8a2021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1008874https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Respiratory 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.Josua O Aponte-SerranoJordan J A WeaverT J SegoJames A GlazierJason E ShoemakerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 10, p e1008874 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Josua O Aponte-Serrano Jordan J A Weaver T J Sego James A Glazier Jason E Shoemaker Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.
description	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.
format	article
author	Josua O Aponte-Serrano Jordan J A Weaver T J Sego James A Glazier Jason E Shoemaker
author_facet	Josua O Aponte-Serrano Jordan J A Weaver T J Sego James A Glazier Jason E Shoemaker
author_sort	Josua O Aponte-Serrano
title	Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.
title_short	Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.
title_full	Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.
title_fullStr	Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.
title_full_unstemmed	Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.
title_sort	multicellular spatial model of rna virus replication and interferon responses reveals factors controlling plaque growth dynamics.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/665229f699cf4d378040ea345b385a8a
work_keys_str_mv	AT josuaoaponteserrano multicellularspatialmodelofrnavirusreplicationandinterferonresponsesrevealsfactorscontrollingplaquegrowthdynamics AT jordanjaweaver multicellularspatialmodelofrnavirusreplicationandinterferonresponsesrevealsfactorscontrollingplaquegrowthdynamics AT tjsego multicellularspatialmodelofrnavirusreplicationandinterferonresponsesrevealsfactorscontrollingplaquegrowthdynamics AT jamesaglazier multicellularspatialmodelofrnavirusreplicationandinterferonresponsesrevealsfactorscontrollingplaquegrowthdynamics AT jasoneshoemaker multicellularspatialmodelofrnavirusreplicationandinterferonresponsesrevealsfactorscontrollingplaquegrowthdynamics
_version_	1718375780613881856

Multicellular spatial model of RNA virus replication and interferon responses reveals factors controlling plaque growth dynamics.

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