Reprogramming the unfolded protein response for replication by porcine reproductive and respiratory syndrome virus

Gao, Peng; Chai, Yue; Song, Jiangwei; Li, Teng; Chen, Peng; Zhou, Lei; Ge, Xinna; Guo, Xin; Han, Jun; Yang, Hanchun

doi:10.1371/journal.ppat.1008169

Cited by 38 publications

(38 citation statements)

References 82 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2C). To measure total PRRSV RNA, a pair of internal primers in the viral open reading frame 7 (ORF7) gene were used to amplify all subgenomic mRNA and genomic RNA by quantitative real-time PCR (RT-qPCR) (32,33). Axl knockdown did not significantly influence the abundance of PRRSV RNA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus Utilizes Viral Apoptotic Mimicry as an Alternative Pathway To Infect Host Cells

Wei

Qiao

et al. 2020

J Virol

View full text Add to dashboard Cite

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV), has led to enormous economic losses in global swine industry. Infection by PRRSV is previously shown to be via low pH-dependent clathrin-mediated endocytosis (CME) and CD163 functions as an essential receptor during viral infection. Despite much research focusing on it, PRRSV infection remains to be fully elucidated. In this study, we demonstrated that PRRSV externalized phosphatidylserine (PS) on the envelope as viral apoptotic mimicry, and infected host cells through T-cell immunoglobulin and mucin domain (TIM)-induced and CD163-involved macropinocytosis as an alternative pathway. In detail, we identified that PS receptor (PSR) TIM-1/4 recognized and interacted with PRRSV as viral apoptotic mimicry and subsequently induced macropinocytosis by the downstream Rho GTPases Rac1, cell division control protein 42 (Cdc42) and p21-activated kinase 1 (Pak1). Altogether these results expand our knowledge of PRRSV infection, which will support implications for prevention and control of PRRS. IMPORTANCE PRRS has caused huge economic losses to pig farming worldwide. Its causative agent, PRRSV, infects host cells through low pH-dependent CME and CD163 is indispensable during the process. Whether there exist alternative infection pathways for PRRSV arouses our interest. Here, we found that PRRSV exposed PS on its envelope and disguised as apoptotic debris. The PSR TIM-1/4 recognized PRRSV and induced the downstream signaling pathway to mediate viral infection via CD163-dependent macropinocytosis. The current work deepens our understanding of PRRSV infection, and provides clues for the development of drugs and vaccines against the virus.

show abstract

Section: Resultsmentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus Utilizes Viral Apoptotic Mimicry as an Alternative Pathway To Infect Host Cells

Wei

Qiao

et al. 2020

J Virol

View full text Add to dashboard Cite

show abstract

“…Porcine reproductive and respiratory syndrome virus (PRRSV, also known as beta-arterivirus suid 1) infects pigs and inflicts a great economic strain on the farming industry, but frequent antigenic variations have hampered the development of a vaccine [102][103][104][105]. PRRSV primarily infects alveolar macrophages where it inhibits PKR to enable its own replication [102].…”

Section: Other Respiratory Virusesmentioning

confidence: 99%

“…Interestingly, UPR signalling by PERK and IRE1α appears to be more important than PKR in promoting stress granule formation during PRRSV infection [104,105], but PERK may also play a role in severe pneumonias caused by co-infection with PRRSV and bacteria, since the resulting eIF2α phosphorylation inhibits IFN and tumour necrosis factor (TNF) production. Curiously, ISR activation during PRRSV infection might increase viral titres [103]. ATF4 is held in the cytosol by the viral proteins nsp2 and nsp3, preventing its migration to the nucleus.…”

Section: Other Respiratory Virusesmentioning

confidence: 99%

The integrated stress response in pulmonary disease

et al. 2020

View full text Add to dashboard Cite

The respiratory tract and its resident immune cells face daily exposure to stress, both from without and from within. Inhaled pathogens, including severe acute respiratory syndrome coronavirus 2, and toxins from pollution trigger a cellular defence system that reduces protein synthesis to minimise viral replication or the accumulation of misfolded proteins. Simultaneously, a gene expression programme enhances antioxidant and protein folding machineries in the lung. Four kinases (PERK, PKR, GCN2 and HRI) sense a diverse range of stresses to trigger this “integrated stress response”. Here we review recent advances identifying the integrated stress response as a critical pathway in the pathogenesis of pulmonary diseases, including pneumonias, thoracic malignancy, pulmonary fibrosis and pulmonary hypertension. Understanding the integrated stress response provides novel targets for the development of therapies.

show abstract

“…The spliced (XBP1s) and unsliced (XBP1u) forms were analyzed by digesting the RT-PCR products with the restriction enzyme Pst I (FD0615) (Thermo Fisher Scientific, Hampton, NH, USA). Followed by purification of digested PCR products with 1.5% agarose gel electrophoresis and analysis by using the gel imaging system (Federal bioproducts Inc., Manufacturer, UK) [28,42,43].…”

Section: Xbp1 Mrna Splicing Assaymentioning

confidence: 99%

“…Studies have shown that the interaction of dengue virus envelope protein with GRP78, calreticulin, and calnexin promote proper folding and assembly of viral proteins for replication [ 27 ]. The UPR induced by porcine reproductive and respiratory syndrome virus (PRRSV) suppresses viral replication and RNA synthesis [ 28 ]. PERK and IRE1, but not the ATF6 pathway, can be activated by HCMV lytic replication [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Induction of the Unfolded Protein Response during Bovine Alphaherpesvirus 1 Infection

Wang

et al. 2020

Viruses

View full text Add to dashboard Cite

Bovine herpesvirus 1 (BoHV-1) is an alphaherpesvirus that causes great economic losses in the cattle industry. Herpesvirus infection generally induces endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in infected cells. However, it is not clear whether ER stress and UPR can be induced by BoHV-1 infection. Here, we found that ER stress induced by BoHV-1 infection could activate all three UPR sensors (the activating transcription factor 6 (ATF6), the inositol-requiring enzyme 1 (IRE1), and the protein kinase RNA-like ER kinase (PERK)) in MDBK cells. During BoHV-1 infection, the ATF6 pathway of UPR did not affect viral replication. However, both knockdown and specific chemical inhibition of PERK attenuated the BoHV-1 proliferation, and chemical inhibition of PERK significantly reduced the viral replication at the post-entry step of the BoHV-1 life cycle. Furthermore, knockdown of IRE1 inhibits BoHV-1 replication, indicating that the IRE1 pathway may promote viral replication. Further study revealed that BoHV-1 replication was enhanced by IRE1 RNase activity inhibition at the stage of virus post-entry in MDBK cells. Furthermore, IRE1 kinase activity inhibition and RNase activity enhancement decrease BoHV1 replication via affecting the virus post-entry step. Our study revealed that BoHV-1 infection activated all three UPR signaling pathways in MDBK cells, and BoHV-1-induced PERK and IRE1 pathways may promote viral replication. This study provides a new perspective for the interactions of BoHV-1 and UPR, which is helpful to further elucidate the mechanism of BoHV-1 pathogenesis.

show abstract

Reprogramming the unfolded protein response for replication by porcine reproductive and respiratory syndrome virus

Cited by 38 publications

References 82 publications

Porcine Reproductive and Respiratory Syndrome Virus Utilizes Viral Apoptotic Mimicry as an Alternative Pathway To Infect Host Cells

Porcine Reproductive and Respiratory Syndrome Virus Utilizes Viral Apoptotic Mimicry as an Alternative Pathway To Infect Host Cells

The integrated stress response in pulmonary disease

Induction of the Unfolded Protein Response during Bovine Alphaherpesvirus 1 Infection

Contact Info

Product

Resources

About