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Abstract
Recently, we identified a unique -2/-1 ribosomal frameshift mechanism in PRRSV, which yields two truncated forms of nonstructural protein (nsp) 2 variants, nsp2TF and nsp2N. Here, in vitro expression of individual PRRSV nsp2TF and nsp2N demonstrated their ability to suppress cellular innate immune responses in transfected cells. Two recombinant viruses were further analyzed, in which either nsp2TF was C-terminally truncated (vKO1) or expression of both nsp2TF and nsp2N was knocked out (vKO2). Host cellular mRNA profiling showed that a panel of cellular immune genes, in particular those involved in innate immunity, was upregulated in cells infected with vKO1 and vKO2. Compared to the wild-type virus, vKO1 and vKO2 expedited the IFN-α response and increased NK cell cytotoxicity, and subsequently enhanced T cell immune responses in infected pigs. Our data strongly implicate nsp2TF/nsp2N in arteriviral immune evasion and demonstrate that nsp2TF/nsp2N-deficient PRRSV is less capable of counteracting host innate immune responses.
Highlights
The innate immune response provides the first line of defense against intruding pathogens
IFN-β signaling was activated by infection with Sendai virus and the luciferase expression level was measured at 16 h after stimulation
To assess whether these inhibitory effects were directly linked to PLP2's protease/DUB activity, we engineered a panel of constructs in which the PLP2 catalytic residues Cys437 and His506 were both substituted with alanine (C/H > A)
Summary
The innate immune response provides the first line of defense against intruding pathogens. Pathogen-associated molecular patterns, like doublestranded RNA (dsRNA) in the case of RNA virus infection, are recognized by host cell receptors to activate protein signaling cascades, which results in the activation of transcription factors, including IRF3, NF-κB, and ATF-2/c JUN. Their coordinated activation leads to the formation of transcriptionally competent enhanceosomes in the cell nucleus, which induce the expression of type I IFNs. After being secreted from infected cells, type I IFNs bind to receptors on the surface of adjacent cells to activate the so-called JAK-STAT signaling pathway. This induces the transcription of a range of interferon-stimulated genes (ISGs), whose products function as effector molecules in the host cell response to viral infection (Raftery and Stevenson, 2017; Schoggins and Rice, 2011)
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