Inhibition of Rabies Virus by 1,2,3,4,6-Penta-O-galloyl-β-d-Glucose Involves mTOR-Dependent Autophagy

Tu, Zhongzhong; Gong, Wenjie; Zhang, Yan; Feng, Ye; Liu, Yan; Tu, Changchun

doi:10.3390/v10040201

Cited by 25 publications

(19 citation statements)

References 53 publications

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“…Many viruses, including those of fish, activate/need autophagy to replicate 58,59,66,[78][79][80] . In this regard, there are some previous studies that have analysed the influence of autophagy on SVCV infection 54,57,58 ; however, the conclusions of these studies are contradictory with respect to the activation of autophagy as either a negative regulatory mechanism 54,57 or, as determined more recently, a mechanism required by the virus for replication 58 .…”

Section: Discussionmentioning

confidence: 99%

Zebrafish C-reactive protein isoforms inhibit SVCV replication by blocking autophagy through interactions with cell membrane cholesterol

Belló-Pérez

Pereiro

Coll

et al. 2020

Sci Rep

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Phosphorylcholine works not only as a pathogen-associated molecular pattern (PAMP) 10,18-20 , but also as a danger-associated molecular pattern (DAMP) 18,21-24. This phosphorylcholine-binding site of the soluble CRP is also involved in interactions with, for instance, oxidized low-density lipoprotein (LDL) 21 , nuclear materials (such as chromatin, histones, small nuclear ribonucleoproteins) 25,26 , and other compounds that may not contain phosphorylcholine but are abundant in bacteria 27 , fungi 28,29 and parasites 30,31. In mammals, CRPs are usually triggered during both viral and bacterial infections 32 , although associated serum CRP level increases are more characteristic of bacterial infections, during which they increase by 3-fold logs, while viruses induce lower but significant 10 1 serum CRP levels 2,32,33. Furthermore, the few existing studies that have analysed C-reactive-like protein (CRP) levels in fish show moderate serum level increases in response to both bacterial and viral infections, suggesting an antiviral effect for CRPs 34-36. For example, in common carp (Cyprinus carpio), the serum CRP levels increase up to 2-, 6-and 10-fold in response to Aeromonas salmonicida 37 , Aeromonas hydrophila 34 and cyprinid herpesvirus-3 (CyHV-3) 35 infections, respectively. Further positive correlations between CRP levels and viral infections have been established in fish by transcriptional analysis. For instance, significant upregulation of crp gene expression in several immune-and non-immune-related tissues of diverse fish species has been revealed in response to viruses such as CyHV-3 35 , red seabream iridovirus (RSIV) 38-40 , viral haemorrhagic septicaemia virus (VHSV) 41,42 and spring viraemia of carp virus (SVCV) 42,43. Similarly, higher transcriptional expression of crp genes was observed in common carp treated with polyinosinic:polycytidylic acid (polyI:C, a compound that mimics viral dsRNA) 36 , in DNA-vaccinated rainbow trout (Oncorhynchus mykiss) 44 and zebrafish (Danio rerio) embryos microinjected with an expression plasmid encoding the il6 gene 42 , a cytokine that is upregulated in response to viral infections in humans 45. In this sense, our recent findings show that all previously identified zebrafish CRP1-7 isoforms 46 confer isoform-dependent anti-SVCV protection in vitro and in vivo 47 and exert unexpected anti-SVCV synergistic effects 47 with 25-hydroxycholesterol (25-HOC) 48. Recombinant CRP from tongue sole (Cynoglossus semilaevis) has also been reported to enhance host resistance to RSIV infection when intraperitoneally (i.p.) co-injected with the virus inoculum 40. However, despite the great relevance for evolutionary immunology and therapeutic potential of CRPs, the underlying mechanisms for CRP antiviral effects are not yet known. The present work has been focused on these mechanistic aspects. Results CRP1-7 anti-SVCV activity targets host cells rather than the virus. Our previous studies showed that the treatment with the supernatant from epithelioma papulosum cyprinid (EPC) cells th...

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Section: Discussionmentioning

confidence: 99%

Zebrafish C-reactive protein isoforms inhibit SVCV replication by blocking autophagy through interactions with cell membrane cholesterol

Belló-Pérez

Pereiro

Coll

et al. 2020

Sci Rep

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“…PGG took longer to reach the blood stream than other polyphenolic compounds and eventually existed in free form; plasma concentration of PGG was 3–4 μ M 2 hours post-injection. Similarly, PGG has been delivered in small animal models via IP routes for anxiolytic properties, 44 anti-viral treatment, 14,178 anti-tumor studies, 67,91 and anti-diabetic treatments. 186 Furthermore, PGG dosages up to 10 mg/kg have been used for the inhibition of capillary morphogenesis gene 2 in mice via the IP route.…”

Section: Current Issues With Pgg Administrationmentioning

confidence: 99%

Pentagalloyl Glucose and Its Functional Role in Vascular Health: Biomechanics and Drug-Delivery Characteristics

et al. 2018

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Pentagalloyl glucose (PGG) is an elastin-stabilizing polyphenolic compound that has significant biomedical benefits, such as being a free radical sink, an anti-inflammatory agent, anti-diabetic agent, enzymatic resistant properties, etc. This review article focuses on the important benefits of PGG on vascular health, including its role in tissue mechanics, the different modes of pharmacological administration (e.g., oral, intravenous and endovascular route, intraperitoneal route, subcutaneous route, and nanoparticle based delivery and microbubble-based delivery), and its potential therapeutic role in vascular diseases such as abdominal aortic aneurysms (AAA). In particular, the use of PGG for AAA suppression and prevention has been demonstrated to be effective only in the calcium chloride rat AAA model. Therefore, in this critical review we address the challenges that lie ahead for the clinical translation of PGG as an AAA growth suppressor.

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“…Our previous study reported that PGG exhibits strong anti-RABV activity and multiple effects on the RABV life cycle (12). However, more studies were required to explore the underlying antiviral mechanisms of PGG, which would better promote its clinical application.…”

Section: Discussionmentioning

confidence: 99%

“…Sample collection and mouse experiments were approved by the Administrative Committee on Animal Welfare of the Institute of Military Veterinary, China (Laboratory Animal Care and Use Committee Authorization, permit number JSY-DW-2016-02). Mice were randomly divided into 4 groups (n ϭ 51), with mouse infection and administration being conducted as described previously (12), Briefly, the mice were injected intramuscularly (i.m.) in both hind legs with a lethal dose of CVS-11 (10 50% lethal doses, 10 6.5 TCID 50 ) and 1 h later with intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have explored the mechanisms by which PGG exerts its biofunctions, including inhibition of viral enzymes, such as the integrase and reverse transcriptase of human immunodeficiency virus type 1 (HIV-1), inducing autophagy via the mTOR/p70S6K-dependent signaling pathway, and downregulating cofilin 1 and inhibiting herpes simplex virus 1 (HSV-1) infection (4). Our previous study revealed that PGG has potent anti-RABV efficacy (12), although the mechanism was not fully elucidated.…”

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confidence: 99%

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Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway

Zhang

et al. 2019

J Virol

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Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3′ untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3. IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3′ UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo. Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.

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Inhibition of Rabies Virus by 1,2,3,4,6-Penta-O-galloyl-β-d-Glucose Involves mTOR-Dependent Autophagy

Cited by 25 publications

References 53 publications

Zebrafish C-reactive protein isoforms inhibit SVCV replication by blocking autophagy through interactions with cell membrane cholesterol

Zebrafish C-reactive protein isoforms inhibit SVCV replication by blocking autophagy through interactions with cell membrane cholesterol

Pentagalloyl Glucose and Its Functional Role in Vascular Health: Biomechanics and Drug-Delivery Characteristics

Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway

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