Nonsteroidal Anti-inflammatory Drugs Potently Inhibit the Replication of Zika Viruses by Inducing the Degradation of AXL

Pan, Ting; Peng, Zhilin; Tan, Likai; Zou, Fan; Zhou, Nan; Liu, Bingfeng; Liang, Liting; Chen, Cancan; Li, Jun; Wu, Liyang; Liu, Guangyan; Peng, Ziwen; Liu, Weiwei; Ma, Xiancai; Zhang, Junsong; Zhu, Xun; Liu, Ting; Li, Mengfeng; Huang, Xi; Tao, Liang; Zhang, Yiwen; Zhang, Hui

doi:10.1128/jvi.01018-18

Cited by 50 publications

(43 citation statements)

References 48 publications

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“…The ORF8 S mutant expressing plasmid was constructed via a PCR-based mutagenesis method from pcDNA3.1-ORF8-HA by introducing a point mutation (L to S) at the 84 amino acid. The green fluorescent protein (gfp) coding sequence was at the 3’ terminus and constructed into the pcDNA3.1 vector 47 . The IRES-GFP sequence was inserted into 3’ ORF8-HA and named ORF8-GFP.…”

Section: Methodsmentioning

confidence: 99%

“…Co-IP assay were performed as our previously described 47 . In brief, HEK293T cells were lysed with NP40 lysis buffer (10 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.5% NP-40, 1% Triton X-100, 10% glycerol, 2 Mm EDTA, 1 mM Na3VO4, 1% protease inhibitor cocktail (Sigma-Aldrich) and phosphatase inhibitor cocktail (TOPSCIENCE) for 30 min on ice with briefly vertaxing every 10 min.…”

Section: Methodsmentioning

confidence: 99%

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The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Zhang

Chen

et al. 2020

Preprint

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189

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SARS-CoV-2 infection have caused global pandemic and claimed over 5,000,000 tolls [1][2][3][4] . Although the genetic sequences of their etiologic viruses are of high homology, the clinical and pathological characteristics of COVID-19 significantly differ from SARS 5,6 . Especially, it seems that SARS-CoV-2 undergoes vast replication in vivo without being effectively monitored by anti-viral immunity 7 . Here, we show that the viral protein encoded from open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all the viral proteins, can directly interact with MHC-I molecules and significantly down-regulates their surface expression on various cell types. In contrast, ORF8a and ORF8b of SARS-CoV do not exert this function. In the ORF8-expressing cells, MHC-I molecules are selectively target for lysosomal degradation by an autophagy-dependent mechanism.As a result, CTLs inefficiently eliminate the ORF8-expressing cells. Our results demonstrate that ORF8 protein disrupts antigen presentation and reduces the recognition and the elimination of virus-infected cells by CTLs 8 . Therefore, we suggest that the inhibition of ORF8 function could be a strategy to improve the special immune surveillance and accelerate the eradication of SARS-CoV-2 in vivo.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Zhang

Chen

et al. 2020

Preprint

Self Cite

189

208

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“…In addition to the antiviral activity against SARS-CoV-2 virus demonstrated here, naproxen also exhibited antiviral properties in cellular and rodent models of Influenza A and B 6,10,26 . Naproxen also inhibited the replication of the unrelated Zika virus 27 . Therefore, from three unrelated single-stranded RNA virus, we suggest that naproxen could present broad-spectrum antiviral properties.…”

Section: Naproxen Inhibits Sars-cov-2 Infection In Veroe6 Cells and Imentioning

confidence: 97%

Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

Terrier

Dilly

Pizzorno

et al. 2020

Preprint

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There is an urgent need for specific antiviral drugs directed against SARS-CoV-2 both to prevent the most severe forms of COVID-19 and to reduce viral excretion and subsequent virus dissemination; in the present pandemic context, drug repurposing is a priority. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus in order to inhibit its association with viral RNA could be a strategy to impeding viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, belonging to the NSAID family, previously demonstrated against Influenza A virus, were evaluated against SARS-CoV-2. Naproxen binding to the nucleoprotein of SARS-CoV2 was shown by molecular modeling. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2 induceddamage. The benefit of naproxen addition to the standard of care is tested in an on-going clinical study.

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“…Zika virus titers were determined by a plaque assay performed on Vero cells by following the procedures as described previously [10]. Briefly, Vero cells were seeded in 12 well plates and used for infection when the cells were grown to 90% confluence.…”

Section: Zikv Titration and Plaque Assaymentioning

confidence: 99%

“…However, many ISGs are still undiscovered, and their antiviral mechanisms need to be further investigated and thoroughly characterized. Recent studies have indicated that several ISGs, such as IFITM1 [9], IFITM3 [9], PARP12 [10] and Viperin [11] could inhibit ZIKV replication. A recent high-throughput cDNA library derived from type I IFN-treated human cells screen was used to identify a set of genes that form a novel regulatory network of host factors that mediates antiviral effects [12,13].…”

Section: Introductionmentioning

confidence: 99%

C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

Yang

Yao

et al. 2020

PLoS Negl Trop Dis

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The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention. "Guangdong Te Zhi program" youth science and technology talent of project (2015TQ01R281); Guangdong MEDP Fund Author summary ZIKV represents a serious threat to global health with particular relevance to microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. Despite the global health threat of Zika virus infection, there is currently no vaccine or effective antiviral therapy available for the disease. As widely recognized, interferon signaling is key to establishing a strong antiviral state in host cells, mainly mediated through the anti-viral effects of numerous interferon-stimulated genes (ISGs). This work described our novel finding of the antiviral effect of a novel ISG, C19orf66, and its underlying mechanisms. We identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically interacting and colocalizing with the ZIKV nonstructural (NS) protein NS3, which inducing NS3 degradation via a lysosome-dependent pathway. Thus, this work broadens the understanding of the pivotal roles of C19orf66 in the interaction between the host and ZIKV, which might further provide a rational basis for developing novel anti-ZIKV strategies. PLOS NEGLECTED TROPICAL DISEASESC19orf66 suppresses ZIKV replication by target viral NS3 PLOS Neglected Tropical Diseases | https://doi.org/10.

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Nonsteroidal Anti-inflammatory Drugs Potently Inhibit the Replication of Zika Viruses by Inducing the Degradation of AXL

Cited by 50 publications

References 48 publications

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

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