Severe Acute Respiratory Syndrome Coronavirus nsp1 Suppresses Host Gene Expression, Including That of Type I Interferon, in Infected Cells

Narayanan, Krishna; Huang, Cheng; Lokugamage, Kumari G.; Kamitani, Wataru; Ikegami, Tetsuro; Tseng, Chien Te K.; Makino, Shinji

doi:10.1128/jvi.02472-07

Cited by 417 publications

(554 citation statements)

References 57 publications

(79 reference statements)

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“…These findings highlight the importance of vhs in controlling host immune responses to HSV. Likewise, Narayanan et al showed that SARS-CoV nsp1 suppresses host gene expression in infected cells, including the expression of the type I IFN gene and ISGs like those encoding beta interferon (IFN-␤), ISG15, and ISG56 (9). It has also been reported that SARS-CoV nsp1 plays a role in the interruption of the IFN signaling pathway by decreasing the phosphorylation of STAT1 and is necessary for efficient viral growth in the human lung epithelial cell line Calu-3 (10).…”

Section: Virus-induced Host Protein Shutoff Is Considered To Be a Majmentioning

confidence: 99%

Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses

Hayashi

MacDonald

Takimoto

2015

J Virol

104

143

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Influenza virus infection causes global inhibition of host protein synthesis in infected cells. This host shutoff is thought to allow viruses to escape from the host antiviral response, which restricts virus replication and spread. Although the mechanism of host shutoff is unclear, a novel viral protein expressed by ribosomal frameshifting, PA-X, was found to play a major role in influenza virus-induced host shutoff. However, little is known about the impact of PA-X expression on currently circulating influenza A virus pathogenicity and the host antiviral response. In this study, we rescued a recombinant influenza A virus, A/California/ 04/09 (H1N1, Cal), containing mutations at the frameshift motif in the polymerase PA gene (Cal PA-XFS). Cal PA-XFS expressed significantly less PA-X than Cal wild type (WT). Cal WT, but not Cal PA-XFS, induced degradation of host ␤-actin mRNA and suppressed host protein synthesis, supporting the idea that PA-X induces host shutoff via mRNA decay. Moreover, Cal WT inhibited beta interferon (IFN-␤) expression and replicated more rapidly than Cal PA-XFS in human respiratory cells. Mice infected with Cal PA-XFS had significantly lower levels of viral growth and greater expression of IFN-␤ mRNA in their lungs than mice infected with Cal WT. Importantly, more antihemagglutinin and neutralizing antibodies were produced in Cal PA-XFSinfected mice than in Cal WT-infected mice, despite the lower level of virus replication in the lungs. Our data indicate that PA-X of the pandemic H1N1 virus has a strong impact on viral growth and the host innate and acquired immune responses to influenza virus. IMPORTANCEVirus-induced host protein shutoff is considered to be a major factor allowing viruses to evade innate and acquired immune recognition. We provide evidence that the 2009 H1N1 influenza A virus protein PA-X plays a role in virus replication and inhibition of host antiviral response by means of its host protein synthesis shutoff activity both in vitro and in vivo. We also demonstrated that, while the growth of Cal PA-XFS was attenuated in the lungs of infected animals, this mutant induced a stronger humoral response than Cal WT. Our findings clearly highlight the importance of PA-X in counteracting the host innate and acquired immune responses to influenza virus, an important global pathogen. This work demonstrates that inhibition of PA-X expression in influenza virus vaccine strains may provide a novel way of safely attenuating viral growth while inducing a more robust immune response.

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Section: Virus-induced Host Protein Shutoff Is Considered To Be a Majmentioning

confidence: 99%

Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses

Hayashi

MacDonald

Takimoto

2015

J Virol

104

143

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Section: Introductionmentioning

confidence: 99%

“…Secreted IFN binds to the IFN receptor and activates a JAK/STAT signalling pathway, upregulating the expression of a subset of genes that impede virus replication (Randall & Goodbourn, 2008). However, many viruses have evolved mechanisms to circumvent the IFN response (Blakqori et al, 2007;Jennings et al, 2005;Kopecky-Bromberg et al, 2007;Narayanan et al, 2008).Porcine reproductive and respiratory syndrome virus (PRRSV), the causative agent of porcine reproductive and respiratory syndrome, is a small enveloped, singlestranded, positive-sense RNA virus belonging to the family Arteriviridae within the order Nidovirales (Meulenberg, 2000). The genome is about 15.4 kb and contains at least nine ORFs.…”

mentioning

confidence: 99%

The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation

Zheng

Zhou

et al. 2010

Journal of General Virology

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There is growing evidence that porcine reproductive and respiratory syndrome virus (PRRSV) has developed mechanisms to subvert the host innate immune response. PRRSV non-structural protein 2 (Nsp2) was suggested previously as a potential interferon (IFN) antagonist. This study focused on Nsp2 to investigate its inhibitory mechanism of IFN induction. It was demonstrated that Nsp2 strongly inhibited IFN-b production by antagonizing activation of the IFN regulatory factor 3 (IRF-3) pathway induced by the Sendai virus (SeV). Further studies revealed that the cysteine protease domain (PL2) of Nsp2 was necessary for IFN antagonism. Additionally, both full-length Nsp2 and the PL2 protease domain of Nsp2 were found to inhibit SeV-induced phosphorylation and nuclear translocation of IRF-3. These findings suggest that Nsp2 is likely to play an important role in subversion of IRF-3-dependent innate antiviral defences, providing a basis for elucidating the mechanisms underlying PRRSV pathogenesis. INTRODUCTIONThe production of type I interferons (IFN-a/b) plays a pivotal role in the host antiviral immune defence (Bonjardim, 2005). Cellular sensors capable of recognizing various viral determinants initiate IFN signal transduction. Positive-stranded RNA viruses can generate intermediate dsRNA during replication, which is an efficient inducer of type I IFNs. This intermediate dsRNA can trigger a cascade of cellular sensors, resulting in type I IFN production and secretion (Kawai & Akira, 2006a;Randall & Goodbourn, 2008). The induction of type I IFNs is initiated via recognition of a pathogen-associated molecule in dsRNA by cellular pattern recognition receptors, including Tolllike receptor 3 (TLR3), caspase recruitment domain (CARD)-containing proteins, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 . TLR3 signals through the adaptor molecule Toll-interleukin-1-resistance domain-containing adaptor inducing IFN-b (TRIF), whilst MDA-5 and RIG-I signal through the adaptor molecule mitochondrial antiviral signal protein (MAVS; also known as IPS-1, Cardif and VISA) to activate a type I IFN response (Kawai & Akira, 2006b; Kawai et al., 2005; Yamamoto et al., 2003). Despite utilizing different adaptors, both pathways converge to activate two downstream kinases, TANK-binding kinase 1 (TBK-1) and inhibitor of kB kinase e (IKKe), subsequently leading to the activation of latent IFN transcription factors, including IFN regulatory factors (IRF-3 and/or IRF-7), nuclear factor-kB (NF-kB) and activating protein 1 (AP-1) (Fitzgerald et al., 2003;Randall & Goodbourn, 2008; Sharma et al., 2003). Activated IFN transcription factors translocate to the nucleus and activate IFN transcription (Biron, 2001). Secreted IFN binds to the IFN receptor and activates a JAK/STAT signalling pathway, upregulating the expression of a subset of genes that impede virus replication (Randall & Goodbourn, 2008). However, many viruses have evolved mechanisms to circumvent the IFN response (Blakqori et al., 2007;Jennings et al.,...

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“…In order to combat the antiviral effects of IFN-a/ b, many viruses, such as coronavirus, have evolved distinct strategies to inhibit IFN signalling pathways for their survival (Haller & Weber, 2007). Human coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), encodes at least six innate immune antagonists, including non-structural protein 1 (nsp1) (Narayanan et al, 2008), the papainlike protease domain in nsp3 (Devaraj et al, 2007), nucleocapsid protein (Kopecky-Bromberg et al, 2007;Lu et al, 2011), membrane protein (Siu et al, 2009) and the products of ORF6 and ORF3b (Kopecky-Bromberg et al, 2007). Our previous work found that human NL63 CoV (HCoV-NL63) (van der Hoek et al, 2005) also encodes a papain-like protease, termed PLP2, which has deubiquitinase (DUB) activity and antagonizes IFN induction (Chen et al, 2007;Clementz et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

Xing

Chen

et al. 2013

Journal of General Virology

146

170

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Porcine epidemic diarrhea virus (PEDV) is the cause of an economically important swine disease. Previous studies suggested that PEDV does not elicit a robust IFN response, but the mechanism(s) used to evade or block this innate immune response was not known. In this study, we found that PEDV infection blocked synthetic dsRNA-induced IFN-b production by interfering with the activation of interferon regulatory factor 3 (IRF3). We identified PEDV replicase encoded papain-like protease 2 (PLP2) as an IFN antagonist that depends on catalytic activity for its function. We show that levels of ubiquitinated proteins are reduced during PEDV infection and that PEDV PLP2 has deubiquitinase (DUB) activity that recognizes and processes both K-48 and K-63 linked polyubiquitin chains. Furthermore, we found that PEDV PLP2 strongly inhibits RIG-Iand STING-activated IFN expression and that PEDV PLP2 can be co-immunoprecipitated with and deubiquitinates RIG-I and STING, the key components of the signalling pathway for IFN expression. These results show that PEDV infection suppresses production of IFN-b and provides evidence indicating that the PEDV papain-like protease 2 acts as a viral DUB to interfere with the RIG-I-and STING-mediated signalling pathway.

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Severe Acute Respiratory Syndrome Coronavirus nsp1 Suppresses Host Gene Expression, Including That of Type I Interferon, in Infected Cells

Cited by 417 publications

References 57 publications

Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses

Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses

The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation

The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

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