Abstract:Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV) and rabies virus (RABV)… Show more
“…Interestingly, the A11090G, A8679C, and G2686A changes co-occurred in lines L2 and L5, suggesting that they may be an epistatic set. This speculation is substantiated by the fact that G2686A produced a non-conservative (G146E) amino acid replacement in protein M, which is the only VSV protein known to block innate immunity (Faul, Lyles, and Schnell 2009; Rieder and Conzelmann 2009). Figure 4.Effect of the A11090G mutation on the predicted secondary structure of the trailer.…”
Experimental evolution studies have shown that RNA viruses respond rapidly to directional selection and thus can adapt efficiently to changes in host cell tropism, antiviral drugs, or other imposed selective pressures. However, the evolution of RNA viruses under relaxed selection has been less extensively explored. Here, we evolved vesicular stomatitis virus in mouse embryonic fibroblasts knocked-out for PKR, a protein with a central role in antiviral innate immunity. Vesicular stomatitis virus adapted to PKR-negative mouse embryonic fibroblasts in a gene-specific manner, since the evolved viruses exhibited little or no fitness improvement in PKR-positive cells. Full-length sequencing revealed the presence of multiple parallel nucleotide substitutions arising in independent evolution lines. However, site-directed mutagenesis showed that the effects of these substitutions were not PKR dependent. In contrast, we found evidence for sign epistasis, such that a given substitution which was positively selected was strongly deleterious when tested as a single mutation. Our results suggest that virus evolution in cells with specific innate immunity defects may drive viral specialization. However, this process is not deterministic at the molecular level, probably because the fixation of mutations which are tolerated under a relaxed selection regime is governed mainly by random genetic drift.
“…Interestingly, the A11090G, A8679C, and G2686A changes co-occurred in lines L2 and L5, suggesting that they may be an epistatic set. This speculation is substantiated by the fact that G2686A produced a non-conservative (G146E) amino acid replacement in protein M, which is the only VSV protein known to block innate immunity (Faul, Lyles, and Schnell 2009; Rieder and Conzelmann 2009). Figure 4.Effect of the A11090G mutation on the predicted secondary structure of the trailer.…”
Experimental evolution studies have shown that RNA viruses respond rapidly to directional selection and thus can adapt efficiently to changes in host cell tropism, antiviral drugs, or other imposed selective pressures. However, the evolution of RNA viruses under relaxed selection has been less extensively explored. Here, we evolved vesicular stomatitis virus in mouse embryonic fibroblasts knocked-out for PKR, a protein with a central role in antiviral innate immunity. Vesicular stomatitis virus adapted to PKR-negative mouse embryonic fibroblasts in a gene-specific manner, since the evolved viruses exhibited little or no fitness improvement in PKR-positive cells. Full-length sequencing revealed the presence of multiple parallel nucleotide substitutions arising in independent evolution lines. However, site-directed mutagenesis showed that the effects of these substitutions were not PKR dependent. In contrast, we found evidence for sign epistasis, such that a given substitution which was positively selected was strongly deleterious when tested as a single mutation. Our results suggest that virus evolution in cells with specific innate immunity defects may drive viral specialization. However, this process is not deterministic at the molecular level, probably because the fixation of mutations which are tolerated under a relaxed selection regime is governed mainly by random genetic drift.
“…Furthermore, antiviral activity of Mx proteins in fish has also been demonstrated from Atlantic salmon Mx1 protein that suppressed infectious pancreatic necrosis virus (IHNV) replication [27], and from olive flounder Mx protein that inhibit replication of two novirhabdoviruses, hirame rhabdovirus (HIRRV) and VHSV [28]. In mammalian rhabdoviruses, such as vesicular stomatitis virus and rabies virus, several mechanisms that can antagonize type I interferon response have been reported, which results in proliferation of the viruses in their hosts [29]. However, there has been no report in VHSV on the viral interfering mechanisms against host's type I interferon response.…”
“…M protein induces global inhibition of host gene expression at the levels of transcription, nuclear-cytoplasmic RNA transport, and translation (reviewed in reference 1). This activity of M protein effectively inhibits the synthesis of most cellular proteins, including type I interferon (IFN) and other antiviral gene products (2,3), thus promoting virus replication. M protein mutations that inactivate its ability to suppress host responses without affecting virus assembly or replication (4) attenuate VSV pathogenicity in vivo (5,6).…”
Inhibition of host-directed gene expression by the matrix (M) protein of vesicular stomatitis virus (VSV) effectively blocks host antiviral responses, promotes virus replication, and disables the host cell. However, dendritic cells (DC) have the capacity to resist these effects and remain functional during VSV infection. Here, the mechanisms of DC resistance to M protein and their subsequent maturation were addressed. Flt3L-derived murine bone marrow dendritic cells (FDC), which phenotypically resemble resident splenic DC, continued to synthesize cellular proteins and matured during single-cycle (high-multiplicity) and multicycle (low-multiplicity) infection with VSV. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived myeloid DC (GDC), which are susceptible to M protein effects, were nevertheless capable of maturing, but the response was delayed and occurred only during multicycle infection. FDC resistance was manifested early and was type I interferon (IFN) receptor (IFNAR) and MyD88 independent, but sustained resistance required IFNAR. MyD88-dependent signaling contributed to FDC maturation during single-cycle infection but was dispensable during multicycle infection. Similar to FDC, splenic DC were capable of maturing in vivo during the first 24 h of infection with VSV, and neither Toll-like receptor 7 (TLR7) nor MyD88 was required. We conclude that FDC resistance to M protein is controlled by an intrinsic, MyD88-independent mechanism that operates early in infection and is augmented later in infection by type I IFN. In contrast, while GDC are not intrinsically resistant, they can acquire resistance during multicycle infection. In vivo, splenic DC resist the inhibitory effects of VSV, and as in multicycle FDC infection, MyD88-independent signaling events control their maturation.
Suppression and evasion of antiviral immune responses are strategies that viruses use to promote their replication in the host organism. Vesicular stomatitis virus (VSV), a prototypic negative-strand RNA virus, utilizes the dual function viral matrix (M) protein to suppress the host response. M protein is a structural protein, but it also suppresses host antiviral responses by inhibiting host-directed gene expression. M protein induces global inhibition of host gene expression at the levels of transcription, nuclear-cytoplasmic RNA transport, and translation (reviewed in reference 1). This activity of M protein effectively inhibits the synthesis of most cellular proteins, including type I interferon (IFN) and other antiviral gene products (2, 3), thus promoting virus replication. M protein mutations that inactivate its ability to suppress host responses without affecting virus assembly or replication (4) attenuate VSV pathogenicity in vivo (5, 6).Immunocompetent animals mount an effective immune response against VSV (7-10), giving rise to the prediction that some innate immune cell types are relatively resistant to the suppressive effects of M protein. We and others have shown that dendritic cells (DC) derived from mur...
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