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

2021 ◽  
Vol 17 (10) ◽  
pp. e1008874
Author(s):  
Josua O. Aponte-Serrano ◽  
Jordan J. A. Weaver ◽  
T. J. Sego ◽  
James A. Glazier ◽  
Jason E. Shoemaker
Keyword(s):  
Rna Virus ◽  
Growth Arrest ◽  
Lung Epithelial Cells ◽  
Type I Interferons ◽  
Sensitivity Analyses ◽  
Cytokine Signaling ◽  
Model Parameters ◽  
Local Concentration ◽  
Type I ◽  
Plaque Growth

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.

scholarly journals Multicellular Spatial Model of RNA Virus Replication and Interferon Responses Reveals Factors Controlling Plaque Growth Dynamics

2021 ◽  
Author(s):  
Josua O. Aponte-Serrano ◽  
Jordan J.A. Weaver ◽  
T.J. Sego ◽  
James A. Glazier ◽  
Jason Edward Shoemaker
Keyword(s):  
Virus Replication ◽  
Rna Virus ◽  
Lung Epithelial Cells ◽  
Sensitivity Analyses ◽  
Cytokine Signaling ◽  
Model Parameters ◽  
Local Concentration ◽  
Type I ◽  
Diffusion Constants ◽  
Plaque Growth

Respiratory viruses present major health challenges, as evidenced by the 2009 influenza pandemic 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 manifestation at the cell and tissue levels are vital to understanding the mechanisms of immunopathology and developing improved, strain independent treatments. Here, we present a novel spatialized multicellular spatial computational model of two principal components of tissue infection and response: RNA virus replication and type-I interferon mediated antiviral response to infection within lung epithelial cells. The model is parameterized using data from influenza virus infected cell cultures and, consistent with experimental observations, exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. Modulating the phosphorylation of STAT or altering the ratio of the diffusion constants of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of arrest on diffusion constants highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro experiments to measure these diffusion constants. Sensitivity analyses were performed under conditions creating both continuous plaque growth and arrested plaque growth. Findings suggest that plaque growth and cytokine assay measurements should be collected during arrested plaque growth, as the model parameters are significantly more sensitive and more likely to be identifiable. The model’s metrics replicate experimental immunostaining imaging and titer based sampling assays. The model is easy to extend to include SARS-CoV-2-specific mechanisms as they are discovered or to include as a component linking epithelial cell signaling to systemic immune models.

scholarly journals Extrachromosomal Histone H2B Mediates Innate Antiviral Immune Responses Induced by Intracellular Double-Stranded DNA

2009 ◽  
Vol 84 (2) ◽  
pp. 822-832 ◽  
Author(s):  
Kouji Kobiyama ◽  
Fumihiko Takeshita ◽  
Nao Jounai ◽  
Asako Sakaue-Sawano ◽  
Atsushi Miyawaki ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rna Virus ◽  
Cellular Signaling ◽  
Helical Structure ◽  
Human Cells ◽  
Type I Interferons ◽  
Type I ◽  
Histone H2b ◽  
Dna Viruses ◽  
Double Stranded Dna

ABSTRACT Fragments of double-stranded DNA (dsDNA) forming a right-handed helical structure (B-DNA) stimulate cells to produce type I interferons (IFNs). While an adaptor molecule, IFN-β promoter stimulator 1 (IPS-1), mediates dsDNA-induced cellular signaling in human cells, the underlying molecular mechanism is not fully understood. Here, we demonstrate that the extrachromosomal histone H2B mediates innate antiviral immune responses in human cells. H2B physically interacts with IPS-1 through the association with a newly identified adaptor, CIAO (COOH-terminal importin 9-related adaptor organizing histone H2B and IPS-1), to transmit the cellular signaling for dsDNA but not immunostimulatory RNA. Extrachromosomal histone H2B was biologically crucial for cell-autonomous responses to protect against multiplication of DNA viruses but not an RNA virus. Thus, the present findings provide evidence indicating that the extrachromosomal histone H2B is engaged in the signaling pathway initiated by dsDNA to trigger antiviral innate immune responses.

PS1-55 Cytokine signaling compromises the sensitivity of melanoma to Type I interferons

Cytokine ◽  
2010 ◽  
Vol 52 (1-2) ◽  
pp. 28-29
Author(s):  
Wei-Chun HuangFu ◽  
Juan Qian ◽  
Chengbao Liu ◽  
Jianghuai Liu ◽  
Vera Ilyin ◽  
...  
Keyword(s):  
Type I Interferons ◽  
Cytokine Signaling ◽  
Type I

scholarly journals MAVS Self-Association Mediates Antiviral Innate Immune Signaling

2009 ◽  
Vol 83 (8) ◽  
pp. 3420-3428 ◽  
Author(s):  
Eric D. Tang ◽  
Cun-Yu Wang
Keyword(s):  
Rna Virus ◽  
Innate Immune ◽  
Type I Interferons ◽  
Mitochondrial Outer Membrane ◽  
Type I ◽  
Rna Helicases ◽  
Downstream Effector ◽  
Innate Immune Signaling ◽  
Self Association ◽  
Tm Domain

ABSTRACT The innate immune system recognizes nucleic acids during viral infection and stimulates cellular antiviral responses. Intracellular detection of RNA virus infection is mediated by the RNA helicases RIG-I (retinoic acid inducible gene I) and MDA-5, which recognize viral RNA and signal through the adaptor molecule MAVS (mitochondrial antiviral signaling) to stimulate the phosphorylation and activation of the transcription factors IRF3 (interferon regulatory factor 3) and IRF7. Once activated, IRF3 and IRF7 turn on the expression of type I interferons, such as beta interferon. Interestingly, unlike other signaling molecules identified in this pathway, MAVS contains a C-terminal transmembrane (TM) domain that is essential for both type I interferon induction and localization of MAVS to the mitochondrial outer membrane. However, the role the MAVS TM domain plays in signaling remains unclear. Here we report the identification of a function for the TM domain in mediating MAVS self-association. The activation of RIG-I/MDA-5 leads to the TM-dependent dimerization of the MAVS N-terminal caspase recruitment domain, thereby providing an interface for direct binding to and activation of the downstream effector TRAF3 (tumor necrosis factor receptor-associated factor 3). Our results reveal a role for MAVS self-association in antiviral innate immunity signaling and provide a molecular mechanism for downstream signal transduction.

scholarly journals Control of coronavirus infection through plasmacytoid dendritic-cell–derived type I interferon

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1131-1137 ◽  
Author(s):  
Luisa Cervantes-Barragan ◽  
Roland Züst ◽  
Friedemann Weber ◽  
Martin Spiegel ◽  
Karl S. Lang ◽  
...  
Keyword(s):  
Response Pattern ◽  
Hepatitis Virus ◽  
Rna Virus ◽  
Plasmacytoid Dendritic Cell ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifns ◽  
Rapid Production ◽  
Coronavirus Infection

Abstract This study demonstrates a unique and crucial role of plasmacytoid dendritic cells (pDCs) and pDC-derived type I interferons (IFNs) in the pathogenesis of mouse coronavirus infection. pDCs controlled the fast replicating mouse hepatitis virus (MHV) through the immediate production of type I IFNs. Recognition of MHV by pDCs was mediated via TLR7 ensuring a swift IFN-α production following encounter with this cytopathic RNA virus. Furthermore, the particular type I IFN response pattern was not restricted to the murine coronavirus, but was also found in infection with the highly cytopathic human severe acute respiratory syndrome (SARS) coronavirus. Taken together, our results suggest that rapid production of type I IFNs by pDCs is essential for the control of potentially lethal coronavirus infections.

scholarly journals ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3

2020 ◽  
Vol 12 (4) ◽  
pp. 251-262
Author(s):  
Ru Zang ◽  
Huan Lian ◽  
Xuan Zhong ◽  
Qing Yang ◽  
Hong-Bing Shu
Keyword(s):  
Rna Virus ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Antiviral Genes ◽  
Ligand Stimulation ◽  
Tlr3 Ligand Poly ◽  
Receptor Domain

Abstract Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3−/− mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.

scholarly journals A mutation in POLR3E impairs antiviral immune response and RNA polymerase III

2020 ◽  
Vol 117 (36) ◽  
pp. 22113-22121
Author(s):  
Aravind Ramanathan ◽  
Michael Weintraub ◽  
Natalie Orlovetskie ◽  
Raphael Serruya ◽  
Dhivakar Mani ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Virus ◽  
Rna Polymerase Iii ◽  
Innate Immune ◽  
Type I Interferons ◽  
Homozygous Mutation ◽  
Type I ◽  
Protein Subunit ◽  
Antiviral Immune Response ◽  
Pol Iii

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

scholarly journals IFI16 Inhibits Porcine Reproductive and Respiratory Syndrome Virus 2 Replication in a MAVS-Dependent Manner in MARC-145 Cells

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1160 ◽  
Author(s):  
Xiaobo Chang ◽  
Xibao Shi ◽  
Xiaozhuan Zhang ◽  
Li Wang ◽  
Xuewu Li ◽  
...  
Keyword(s):  
Rna Virus ◽  
Inhibitory Effect ◽  
Type I Interferons ◽  
Respiratory Syndrome Virus ◽  
Type I ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Antiviral Protein ◽  
Inducible Protein ◽  
Mitochondrial Antiviral Signaling

Porcine reproductive and respiratory syndrome virus (PRRSV) is a single-stranded positive-sense RNA virus, and the current strategies for controlling PRRSV are limited. Interferon gamma-inducible protein 16 (IFI16) has been reported to have a broader role in the regulation of the type I interferons (IFNs) response to RNA and DNA viruses. However, the function of IFI16 in PRRSV infection is unclear. Here, we revealed that IFI16 acts as a novel antiviral protein against PRRSV-2. IFI16 could be induced by interferon-beta (IFN-β). Overexpression of IFI16 could significantly suppress PRRSV-2 replication, and silencing the expression of endogenous IFI16 by small interfering RNAs led to the promotion of PRRSV-2 replication in MARC-145 cells. Additionally, IFI16 could promote mitochondrial antiviral signaling protein (MAVS)-mediated production of type I interferon and interact with MAVS. More importantly, IFI16 exerted anti-PRRSV effects in a MAVS-dependent manner. In conclusion, our data demonstrated that IFI16 has an inhibitory effect on PRRSV-2, and these findings contribute to understanding the role of cellular proteins in regulating PRRSV replication and may have implications for the future antiviral strategies.

scholarly journals MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Siqi Liu ◽  
Jueqi Chen ◽  
Xin Cai ◽  
Jiaxi Wu ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Rna Virus ◽  
Mitochondrial Protein ◽  
Type I Interferons ◽  
Signaling Cascades ◽  
Type I ◽  
Virus Infections ◽  
Binding Motifs ◽  
E3 Ligases ◽  
Signaling Complex ◽  
Irf3 Activation

RNA virus infections are detected by the RIG-I family of receptors, which induce type-I interferons through the mitochondrial protein MAVS. MAVS forms large prion-like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce interferons. Here we show that MAVS polymers recruit several TRAF proteins, including TRAF2, TRAF5, and TRAF6, through distinct TRAF-binding motifs. Mutations of these motifs that disrupted MAVS binding to TRAFs abrogated its ability to activate IRF3. IRF3 activation was also abolished in cells lacking TRAF2, 5, and 6. These TRAF proteins promoted ubiquitination reactions that recruited NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. These results delineate the mechanism of MAVS signaling and reveal that TRAF2, 5, and 6, which are normally associated with NF-κB activation, also play a crucial role in IRF3 activation in antiviral immune responses.

scholarly journals Phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein PINLYP regulates type I interferon innate immunity

2021 ◽  
Vol 119 (1) ◽  
pp. e2111115119
Author(s):  
Zhongshun Liu ◽  
Congwei Jiang ◽  
Zhangmengxue Lei ◽  
Sihan Dong ◽  
Linlin Kuang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Dendritic Cells ◽  
Phospholipase A2 ◽  
Rna Virus ◽  
Cell Types ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Phospholipase A2 Inhibitor

Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaired the activation of IRF3 and production of IFN-β induced by DNA virus, RNA virus, and various Toll-like receptor ligands in multiple cell types. Because PINLYP deficiency in mice engendered an early embryonic lethality in mice, we generated a conditional mouse in which PINLYP was depleted in dendritic cells. Mice lacking PINLYP in dendritic cells were defective in type I IFN induction and more susceptible to lethal virus infection. Thus, PINLYP is a positive regulator of type I IFN innate immunity and important for effective host defense against viral infection.

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