Abstract
The matrix (M) protein of vesicular stomatitis virus (VSV) has a complex role in infection and immune evasion, particularly with respect to suppression of Type I interferon (IFN). Viral strains bearing the wild-type (wt) M protein are able to suppress Type I IFN responses. We recently reported that the 22-25 strain of VSV encodes a wt M protein, however its sister plaque isolate, strain 22-20, carries a M[MD52G] mutation that perturbs the ability of the M protein to block NFκB, but not M-mediated inhibition of host transcription. Therefore, although NFκB is activated in 22-20 infected murine L929 cells infected, no IFN mRNA or protein is produced. To investigate the impact of the M[D52G] mutation on immune evasion by VSV, we used transcriptomic data from L929 cells infected with wt, 22-25, or 22-20 to define parameters in a family of executable logical models with the aim of discovering direct targets of viruses encoding a wt or mutant M protein. After several generations of pruning or fixing hypothetical regulatory interactions, we identified specific predicted targets of each strain. We predict that wt and 22-25 VSV both have direct inhibitory actions on key elements of the NFκB signaling pathway, while 22-20 fails to inhibit this pathway.
Highlights
Viral infection is recognized in the cytoplasm of infected cells by pathogen-associated molecular pattern receptors such as retinoic acid inducible gene-I (RIG-I)
We recently found that the wt M protein alone was sufficient to inhibit virus-driven NFκB activation independently of infection, and that this inhibition was abrogated by the M(M51R) mutation
Transcriptomic data was first filtered for significantly differentially expressed genes by a oneway ANOVA searching for significant variation due to Virus (Mock-infected, 22–20, 22–25, and WT) and/or hours post-infection (HPI) (q
Summary
Viral infection is recognized in the cytoplasm of infected cells by pathogen-associated molecular pattern receptors such as retinoic acid inducible gene-I (RIG-I). This leads to activation of transcription factors, including NFκB, IRF3, and IRF7, that induce antiviral cytokines such as TNF-α, IL-6, and Type I interferons (IFNα and IFNβ) [1,2,3]. RIG-I-dependent activation of IRF3 and consequent IFN gene expression has been well studied in VSV-infected cells [4,5,6]. VSV induces NFκB-dependent expression of many other cytokines, whose activation and suppression have been less well examined. Vesicular stomatitis virus (VSV), the prototypical member of the Rhabdovirus family, has been widely studied as a model system to investigate the mechanisms
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