Dataset Information

Tumor suppressor p53 inhibits porcine epidemic diarrhea virus infection via interferon-mediated antiviral immunity.

ABSTRACT: p53 is a tumor suppressor gene that can be activated in many contexts, such as DNA damage or stressful conditions. p53 has also been shown to be important for responses to certain viral infections. Porcine epidemic diarrhea virus (PEDV) is a major enteric pathogen of the coronavirus family that causes extensive mortality among piglets. The involvement of p53 during PEDV infection has not previously been investigated. In this study, we detected p53 upregulation in response to PEDV infection. Treatment with a p53 specific activator or p53 overexpression markedly decreased viral replication, and we showed that there was more viral progeny produced in p53 knock-out cells than in p53 wild-type cells. Finally, we demonstrated that inhibition of viral infection by p53 was mediated via p53-dependent IFN signaling, leading to IFN-stimulated response element (ISRE) activation, as well as the upregulation of IFN-stimulated genes (ISGs) and IFN-? released from infected cells. These findings demonstrate that p53 suppresses PEDV infection, offering a novel therapeutic strategy for combatting this deadly disease in piglets.

SUBMITTER: Hao Z

PROVIDER: S-EPMC7112615 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor suppressor p53 inhibits porcine epidemic diarrhea virus infection via interferon-mediated antiviral immunity.

Hao Zhichao Z Fu Fang F Cao Liyan L Guo Longjun L Liu Jianbo J Xue Mei M Feng Li L

Molecular immunology 20190218

p53 is a tumor suppressor gene that can be activated in many contexts, such as DNA damage or stressful conditions. p53 has also been shown to be important for responses to certain viral infections. Porcine epidemic diarrhea virus (PEDV) is a major enteric pathogen of the coronavirus family that causes extensive mortality among piglets. The involvement of p53 during PEDV infection has not previously been investigated. In this study, we detected p53 upregulation in response to PEDV infection. Trea ...[more]

PMID: 30784764

Similar Datasets

Project description:UnlabelledPorcine epidemic diarrhea virus (PEDV) is a worldwide-distributed alphacoronavirus, but the pathogenesis of PEDV infection is not fully characterized. During virus infection, type I interferon (IFN) is a key mediator of innate antiviral responses. Most coronaviruses develop some strategy for at least partially circumventing the IFN response by limiting the production of IFN and by delaying the activation of the IFN response. However, the molecular mechanisms by which PEDV antagonizes the antiviral effects of interferon have not been fully characterized. Especially, how PEDV impacts IFN signaling components has yet to be elucidated. In this study, we observed that PEDV was relatively resistant to treatment with type I IFN. Western blot analysis showed that STAT1 expression was markedly reduced in PEDV-infected cells and that this reduction was not due to inhibition of STAT1 transcription. STAT1 downregulation was blocked by a proteasome inhibitor but not by an autophagy inhibitor, strongly implicating the ubiquitin-proteasome targeting degradation system. Since PEDV infection-induced STAT1 degradation was evident in cells pretreated with the general tyrosine kinase inhibitor, we conclude that STAT1 degradation is independent of the IFN signaling pathway. Furthermore, we report that PEDV-induced STAT1 degradation inhibits IFN-α signal transduction pathways. Pharmacological inhibition of STAT1 degradation rescued the ability of the host to suppress virus replication. Collectively, these data show that PEDV is capable of subverting the type I interferon response by inducing STAT1 degradation.ImportanceIn this study, we show that PEDV is resistant to the antiviral effect of IFN. The molecular mechanism is the degradation of STAT1 by PEDV infection in a proteasome-dependent manner. This PEDV infection-induced STAT1 degradation contributes to PEDV replication. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response.

Project description:Porcine epidemic diarrhea virus (PEDV) causes acute and devastating enteric disease in suckling piglets and results in huge economic losses in the pig industry worldwide. To establish productive infection, viruses must first circumvent the host innate immune response. In this study, we found that PEDV infection stimulated epidermal growth factor receptor (EGFR) activation, which has been linked to not only anticancer therapeutics, but also antiviral signaling. Therefore, we determined whether EGFR activation affected PEDV infection by using an activator or overexpression assay. The data showed that EGFR activation enhanced virus replication in both cases. We also found that specific inhibition of EGFR by either inhibitors or small interfering RNA (siRNA) led to a decrease in virus yields. Further analysis revealed that inhibition of EGFR produced augmentation of type I interferon genes. We next observed that the EGFR downstream cascade STAT3 was also activated upon PEDV infection. Similar to the case of EGFR, specific inhibition of STAT3 by either inhibitor or siRNA increased the antiviral activity of interferon and resulted in decreased PEDV RNA levels, and vice versa. The data on STAT3 depletion in combination with EGFR activation suggest that the attenuation of antiviral activity by EGFR activation requires activation of the STAT3 signaling pathway. Taken together, these data demonstrate that PEDV-induced EGFR activation serves as a negative regulator of the type I interferon response and provides a novel therapeutic target for virus infection.IMPORTANCE EGFR is a transmembrane tyrosine receptor that mediates various cellular events, as well as several types of human cancers. In this study, we investigated for the first time the role of EGFR in PEDV infection. We observed that PEDV infection induced EGFR activation. The role of EGFR activation is to impair the antiviral activity of type I interferon, which requires the involvement of the EGFR downstream signaling cascade STAT3. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response, which might serve as a therapeutic target against virus infection.

Dataset Information

Tumor suppressor p53 inhibits porcine epidemic diarrhea virus infection via interferon-mediated antiviral immunity.

Publications

Tumor suppressor p53 inhibits porcine epidemic diarrhea virus infection via interferon-mediated antiviral immunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets