Quercetin Inhibits Hsp70 Blocking of Bovine Viral Diarrhea Virus Infection and Replication in the Early Stage of Virus Infection

Bovine viral diarrhea virus (BVDV), a positive-strand RNA virus of the genus Pestivirus in the Flaviviridae family, is the causative agent of viral diarrheal disease in bovine. BVDV has been used as a surrogate model for the hepatitis C virus (HCV) to evaluate the efficacy of antiviral drugs. The plant flavonol quercetin causes multiple health-promoting effects in humans and animals. It can be made into a variety of additives, and it exerts a variety of immunomodulatory effects with the potential to be used as an antiviral agent. However, quercetin’s antiviral effect and mechanism of action on BVDV are still unclear. Therefore, this study was designed to evaluate quercetin’s effect on BVDV virus replication in vitro and in vivo and elucidate its mechanism of action. A CCK-8 kit was used to analyze the toxicity of the quercetin to the MDBK cells. Western blot, qRT-PCR, TCID50, and histological analysis were used to determine the mechanism of quercetin’s anti-BVDV activity. An oxidative stress kit was used to evaluate the effects of quercetin on ROS, antioxidant enzymes, and MDA indexes. The effect of quercetin on IL-2 and IFN-γ in the serum of mice was determined by using an ELISA kit. The results showed that quercetin inhibits Hsp70, blocks BVDV infection in the early stage of virus infection and inhibits BVDV replication by inhibiting oxidative stress or ERK phosphorylation. In addition, quercetin alleviated the decrease in IFN-γ and IL-2 in the serum of BVDV-infected mice. Quercetin ameliorated BVDV-induced histopathological changes. In summary, this study demonstrated for the first time the role of Hsp70 in BVDV infection and the potential application of quercetin in treating BVDV infection.

[1]  Catherine Legras-Lachuer,et al.  Identification of differentially expressed gene pathways between cytopathogenic and non-cytopathogenic BVDV-1 strains by analysis of the transcriptome of infected primary bovine cells. , 2021, Virology.

[2]  Asma Aktar,et al.  A Review of Medicinal Plants with Antiviral Activity Available in Bangladesh and Mechanistic Insight Into Their Bioactive Metabolites on SARS-CoV-2, HIV and HBV , 2021, Frontiers in Pharmacology.

[3]  G. Orrù,et al.  Quercetin and its derivates as antiviral potentials: A comprehensive review , 2021, Phytotherapy research : PTR.

[4]  Kalyani Korla,et al.  Immunomodulatory Effects of a Concoction of Natural Bioactive Compounds—Mechanistic Insights , 2021, Biomedicines.

[5]  Zhanbo Zhu,et al.  PD-1 Blockade Restores the Proliferation of Peripheral Blood Lymphocyte and Inhibits Lymphocyte Apoptosis in a BALB/c Mouse Model of CP BVDV Acute Infection , 2021, Frontiers in Immunology.

[6]  Natalia S. Adler,et al.  Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus , 2020, Frontiers in Chemistry.

[7]  D. Bayles,et al.  Changes Introduced in the Open Reading Frame of Bovine Viral Diarrhea Virus During Serial Infection of Pregnant Swine , 2020, Frontiers in Microbiology.

[8]  E. Tramontano,et al.  Quercetin Blocks Ebola Virus Infection by Counteracting the VP24 Interferon-Inhibitory Function , 2020, Antimicrobial Agents and Chemotherapy.

[9]  M. Wang,et al.  Quercetin improves immune function in Arbor Acre broilers through activation of NF-κB signaling pathway , 2020, Poultry science.

[10]  Azam Bolhassani,et al.  Heat shock proteins in infection. , 2019, Clinica chimica acta; international journal of clinical chemistry.

[11]  Dae Kim,et al.  ERK-dependent phosphorylation of the linker and substrate-binding domain of HSP70 increases folding activity and cell proliferation , 2019, Experimental & Molecular Medicine.

[12]  Yuan-Lu Cui,et al.  Antioxidant activities of quercetin and its complexes 2 for medicinal application 3 , 2019 .

[13]  J. Rasgon,et al.  Heat shock protein 70 (Hsp70) mediates Zika virus entry, replication, and egress from host cells , 2019, Emerging microbes & infections.

[14]  Min Liu,et al.  Inhibition of JAK2/STAT3 Signaling Pathway Suppresses Proliferation of Burkitt’s Lymphoma Raji Cells via Cell Cycle Progression, Apoptosis, and Oxidative Stress by Modulating HSP70 , 2018, Medical science monitor : international medical journal of experimental and clinical research.

[15]  T. Seya,et al.  DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70 , 2017, Journal of Innate Immunity.

[16]  Y. Bi,et al.  Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection , 2017, Virologica Sinica.

[17]  Lin Gui,et al.  Daphnetin protects oxidative stress-induced neuronal apoptosis via regulation of MAPK signaling and HSP70 expression. , 2016, Oncology letters.

[18]  F. Negro,et al.  Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets , 2016, Scientific Reports.

[19]  R. Andino,et al.  Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection , 2015, Cell.

[20]  Yanming Zhang,et al.  Heat shock protein 70 is associated with CSFV NS5A protein and enhances viral RNA replication. , 2015, Virology.

[21]  M. Bizzarri,et al.  Quercetin Affects Hsp70/IRE1α Mediated Protection from Death Induced by Endoplasmic Reticulum Stress , 2015, Oxidative medicine and cellular longevity.

[22]  Hongmei Wu,et al.  Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies. , 2015, Bioorganic & medicinal chemistry.

[23]  B. Newcomer,et al.  Potential applications for antiviral therapy and prophylaxis in bovine medicine , 2014, Animal Health Research Reviews.

[24]  Yaosheng Chen,et al.  Inhibition of HSP70 reduces porcine reproductive and respiratory syndrome virus replication in vitro , 2014, BMC Microbiology.

[25]  A. Young,et al.  The effect of bovine viral diarrhea virus (BVDV) strains on bovine monocyte-derived dendritic cells (Mo-DC) phenotype and capacity to produce BVDV , 2014, Virology Journal.

[26]  Anand Anbarasu,et al.  Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly , 2013, Bioinformation.

[27]  M. Mustafa,et al.  Antiviral Activity of Baicalein and Quercetin against the Japanese Encephalitis Virus , 2012, International journal of molecular sciences.

[28]  R. Tur-kaspa,et al.  Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity , 2012, Journal of viral hepatitis.

[29]  Kentaro Kato,et al.  Activation of extracellular signal-regulated kinase in MDBK cells infected with bovine viral diarrhea virus , 2009, Archives of Virology.

[30]  Zixue Shi,et al.  Genomic expression profiling of peripheral blood leukocytes of pigs infected with highly virulent classical swine fever virus strain Shimen. , 2009, The Journal of general virology.

[31]  C. Rogier,et al.  Identification of Cellular Proteome Modifications in Response to West Nile Virus Infection* , 2009, Molecular & Cellular Proteomics.

[32]  Rony Seger,et al.  The MEK/ERK cascade: from signaling specificity to diverse functions. , 2007, Biochimica et biophysica acta.

[33]  R. Donis,et al.  Bovine viral diarrhea virus as a surrogate model of hepatitis C virus for the evaluation of antiviral agents. , 2003, Antiviral research.

[34]  K. Kregel,et al.  Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. , 2002, Journal of applied physiology.

[35]  E. Peterhans,et al.  Oxidative stress in cells infected with bovine viral diarrhoea virus: a crucial step in the induction of apoptosis. , 1999, The Journal of general virology.

[36]  P. Moseley,et al.  Heat shock protein 70 regulates cellular redox status by modulating glutathione-related enzyme activities , 2007, Cell stress & chaperones.