High Mobility Group Box 1: a Novel Host Restriction Factor in Zika Virus Replication

doi:10.21203/rs.3.rs-929310/v1

Download PDF

Research Article

High Mobility Group Box 1: a Novel Host Restriction Factor in Zika Virus Replication

https://doi.org/10.21203/rs.3.rs-929310/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Neonatal microcephaly and adult Guillain-Barré syndrome are severe complications of Zika virus (ZIKV) infection. The robustly induced inflammatory cytokine expressions in ZIKV-infected patients may constitute a hallmark for severe disease. In the present study, the potential role of high mobility group box 1 protein (HMGB1) in ZIKV infection was investigated. HMGB1 protein expression was determined by the enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. HMGB1’s role in ZIKV infection was also explored using treatment with dexamethasone, an immunomodulatory drug. Antiviral effects of dexamethasone treatment on both wild-typed (WT) and HMGB1-knockdown (shHMGB1) Huh7 cells were determined by the focus-forming assay. Results showed that the Huh7 cells were highly susceptible to ZIKV infection. The infection was found to induce HMGB1 nuclear-to-cytoplasmic translocation, resulting in a >99% increase in the cytosolic HMGB1 expression at 72h.p.i. The extracellular HMGB1 level was elevated in a time- and multiplicity of infection (MOI)- dependent manner. Dexamethasone 150 µM treatment of the ZIKV-infected cells reduced HMGB1 extracellular release in a dose-dependent manner, with a maximum reduction of 71 ± 5.84% (p < 0.01). The treatment also reduced virus titers by over 83 ± 0.50% (p < 0.01). The antiviral effects, however, was not observed in the dexamethasone-treated HMGB1-knockdown cells, suggesting the importance of the intracellular HMGB1 in ZIKV infection. Overall, these results suggest that translocation of HMGB1 occurred during ZIKV infection and inhibition of the translocation reduced ZIKV replication. These findings highlight the potential of developing therapeutics against ZIKV infection by affecting the translocation of HMGB1 from the nucleus to the cytoplasm.

Infectious Diseases

Virology

microcephaly

syndrome

inflammatory

disease

dexamethasone

Outbreaks involving Zika virus (ZIKV), an arthropod-borne virus (arbovirus) that belongs to the genus Flavivirus, family Flaviviridae, has been declared as Public Health Emergency of International Concern (PHEIC) in February 2016 ¹ following the epidemics in the Pacific and Americas ². ZIKV infection becomes a major concern as it has been associated with severe neurological disorders, including microcephaly in newborns and Guillain-Barré syndrome in adults ^3,4. To date, there is no specific antiviral or vaccine available to treat or prevent ZIKV infection.

HMGB1 is a highly conserved DNA-binding protein and mainly resides in the nucleus, regulating the DNA transcription and nucleosome stability ⁵. During infection and cell injury, acetylated HMGB1 is translocated from the nucleus to the extracellular milieu to act as a proinflammatory cytokine, causing inflammatory responses ⁶ as seen in various virus-infected cells such as hepatitis C virus, dengue virus, West Nile virus, herpes simplex virus, human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2 ^7–13. HMGB1 levels in dengue and hepatitis B infected patients’ sera were found to be positively correlated to viral load and disease symptoms ^14,15. Although the HMGB1 canonical pathway was found to be activated in both in vitro ¹⁶ and ZIKV presymptomatic or asymptomatic patient plasma ¹⁷, the role of HMGB1 in ZIKV infection remains largely unknown.

Dexamethasone is a glucocorticoid that has been broadly used due to its rapid anti-inflammatory and immunosuppressive impacts. The protective role of dexamethasone against various diseases, including sepsis ¹⁸, severe acute pancreatitis ¹⁹, acute lung injury ²⁰ through inhibiting HMGB1-mediated inflammation, has been proposed. Dexamethasone has been shown to inhibit HMGB1 nuclear-to-cytoplasmic translocation via acetyltransferase attenuation, hence reducing the HMGB1-TLR4 inflammatory pathway ²¹. On the other hand, recent studies showed that dexamethasone possesses the antiviral potential against many viruses such as human rhinovirus ²², foot-and-mouth disease virus ²³ and dengue virus ²⁴. The following study aimed to examine the dynamic of HMGB1 expression following ZIKV infection in vitro and its role in the pathogenesis of Zika.

ZIKV caused productive infection in Huh7 cells.

The Huh7 cells were infected with the Asian ZIKV strain P6-740 at multiplicity of infection (MOI) of 1 in a 96-well plate and virus replication was monitored at selected time points for 4 days post-infection. At 24, 48, 72 and 96 h.p.i, two hundred microliters (200 µl) of supernatant of the infected cell cultures was harvested for virus titration using the focus-forming assay as previously described ²⁵. A gradual increase in the production of infectious virus was observed over the infection period (Fig. 1). From a titer of 3 ± 0 log10 FFU/mL at 0 h.p.i, the ZIKV replicated to 3.511 ± 0.033 log10 FFU/mL at 24 h.p.i. (p > 1.0), 4.734 ± 0.010 log10 FFU/mL (1-log increase, p > 1.0) at 48 h.p.i, 5.744 ± 0.012 log10 FFU/mL (2-log increase, p > 0.1) at 72 h.p.i, and a maximum titer of 6.362 ± 0.061 log10 FFU/mL (3-log increase, p < 0.001) at 96 h.p.i (Fig. 1). These findings suggested that Huh7 cells supported ZIKV replication well.

ZIKV infection induced translocation of nuclear HMGB1 into the cytosol.

The nuclear and cytosolic HMGB1 protein expressions of the mock-infected or ZIKV-infected Huh7 cells were determined using immunoblot assay. The nuclear and cytosolic HMGB1 expressions were normalized to the PARP-1 and GAPDH levels, respectively (Fig. 2). The HMGB1 was detected mainly in the nucleus of the mock-infected Huh7 cells after 72 h of incubation period (Fig. 2). During ZIKV infection, the accumulation of nuclear HMGB1 was reduced to 51% at 24 h.p.i (p < 0.01), to 7.2% at 48 h.p.i (p < 0.001) and 0% at 72 h.p.i. (p < 0.001), in comparison to that of the mock-infected Huh7 cells (Fig. 2a). On the other hand, the ZIKV infection resulted in increased level of HMGB1 in the cytoplasm by 11% at 24 h.p.i (p < 0.001), 39% at 48 h.p.i (p < 0.001) and 99% at 72 h.p.i. (p < 0.001) as compared to the mock-infected cells (Fig. 2b). These results suggested that the ZIKV infection induced the translocation of HMGB1 from the nucleus to the cytoplasm in Huh7 cells.

ZIKV infection induced HMGB1 release from Huh7 cells in a time- and MOI-dependent manner.

The extracellular HMGB1 levels in the culture supernatant of mock-infected Huh7 cells remained constant over the 72 h incubation period, with an average value of 346.83 ± 20.19 pg/ml. In contrast, the ZIKV infection at MOI of 1 significantly increased the extracellular HMGB1 levels at 48 h.p.i (1074.75 ± 91.25 pg/ml, p < 0.001) and 72 h.p.i (1397.25 ± 13.75 pg/ml, p < 0.001), in comparison to those of the mock-infected cells (Fig. 3a). Our results also showed that the HMGB1 release from the infected cells was MOI-dependent. At 72 h.p.i, the levels of extracellular HMGB1 increased from 1671.25 ± 162.5 pg/ml (p < 0.05) at MOI of 1, to 2115 ± 81.25 pg/ml (p < 0.05) at MOI of 3 and 8165 ± 531.25 pg/ml (p < 0.001) at MOI of 5 (Fig. 3b).

Dexamethasone inhibited the release of extracellular HMGB1 and ZIKV replication in a dose-dependent manner.

Dexamethasone showed low cytotoxicity for Huh7 cells; almost 100% of the Huh7 were still viable following treatments with 50–200 µM dexamethasone (Fig. 4). After ZIKV infection at MOI of 1, the Huh7 cells were treated with 0, 5, 80 and 150 µM of dexamethasone and the HMGB1 release of infected cell and virus titers were assessed at 72 h.p.i (Figs. 5 and 6). The extracellular HMGB1 levels of ZIKV-infected cells were significantly reduced from 1326 ± 54 pg/ml for the mock treatment, to 829 ± 69 pg/ml (p < 0.05), 564 ± 68 pg/ml (p < 0.01) and 385 ± 93 pg/ml (p < 0.01) by treatment with dexamethasone at 5, 80 and 150 µM, respectively (Fig. 5). Furthermore, the treatment of ZIKV-infected Huh7 cells with 5 µM, 80 µM and 150 µM of dexamethasone decreased the infectious virus titers by 25% (p > 0.05), 67% (P < 0.05) and 83% (1 log, P < 0.01), respectively (Fig. 6), in comparison to the mock-treated control.

Anti-ZIKV effect of dexamethasone was dependent on the presence of HMGB1.

The involvement of HMGB1 in the dexamethasone's anti-ZIKV effect was further investigated using the HMGB1-knockdown cells, shHMGB1 cells (Supplementary Fig. S1). Both shHMGB1 cells and wild-type (WT) Huh7 cells were infected with ZIKV at MOI of 1, followed by treatment with 150 µM of dexamethasone. In general, the ZIKV replicated to higher titer in the shHMGB1 Huh 7 cells than in the WT Huh7 cells (Fig. 7). Dexamethosone treatment of the infected shHMGB1 cells and WT Huh7 cells showed a reduction of 36% (p > 0.05) and 75% of ZIKV titer (P < 0.05), respectively, in comparison to the virus titers in the mock-treated infected cells (Fig. 7). This suggested that the HMGB1 may play a role in the antiviral actions of dexamethasone.

Although the HMGB1 canonical pathway was found to be activated in both in vitro ¹⁶ and ZIKV presymptomatic or asymptomatic patient plasma ¹⁷, there is still no experimental evidence to support these suggestions. The findings of the present study demonstrated that the ZIKV infection induced translocation of HMGB1 from the nucleus to the cytoplasm and release from the infected Huh7 cells. Treatment with dexamethasone, a well-known anti-inflammatory drug, significantly reduced ZIKV infection and the extracellular HMGB1 levels. In the HMGB1 knockdown Huh7 cells, however, the treatment with dexamethasone did not cause significant inhibition of ZIKV replication, suggesting the involvement of HMGB1 in regulating the antiviral mechanisms of dexamethasone (Fig. 8).

HMGB1 is a nuclear transcription factor which acts as a pro-inflammatory cytokine when released from the cells in response to infection, cell injury and inflammation ^6,26. In normal circumstances, the HMGB1 accumulates in the nucleus, giving a nuclear-to-cytoplasmic HMGB1 ratio of approximately 30:1 ²⁷. During infection or cell injury, HMGB1 undergoes post-translational modifications, including acetylation, methylation and phosphorylation, causing its translocation from the nucleus to cytoplasm before being released into the extracellular environment ^28,29. For instance, the host cell p300/CBP-associated factor (PCAF) acetylase complex, triggered by dengue virus capsid protein, has been demonstrated to enhance the HMGB1 release ³⁰. Moreover, excessive production of reactive oxygen species (ROS) induced by respiratory syncytial virus and porcine circovirus-2 have been found to promote the release of HMGB1 ^31,32. Similarly, our study showed that ZIKV infection could induce HMGB1 nuclear-to-cytoplasmic translocation and release in a time-dependent manner, most likely through the similar mechanisms described.

In the previous study, augmented serum levels of HMGB1 was observed in secondary dengue virus infection ¹⁵, which has been associated with higher viral load and prolonged viremia, most probably due to the delayed virus clearance as reported earlier ³³. Meanwhile, our study also revealed that the secreted HMGB1 was elevated in MOI- dependent manner. Because virus-induced cell death is mainly infectious dose-dependent, ZIKV infection may result in necrosis- or apoptosis-dependent HMGB1 passive release, which requires further confirmation in the future.

Extracellular HMGB1 induces innate immune response via interaction with the receptor for advanced glycation end products (RAGE) or toll-like receptor (TLR-2 and − 4), activating MyD88 and NF-κB signaling pathways, which then leads to the production of pro-inflammatory cytokines for virus clearance ³⁴. However, excessive extracellular HMGB1 during virus infection has been associated with the pathogenesis of diseases ^35–37. For instance, extracellular HMGB1 was related to the pathogenesis of dengue hemorrhagic fever-dengue shock syndrome (DHF/DSS), presumably through the vascular barrier disruption ³⁰. Besides, extracellular HMGB1 has been correlated to neuroinvasion of ZIKV and Japanese encephalitis virus (JEV), possibly via disruption of the blood-brain barrier ^38,39. Therefore, preventing the overproduction of extracellular HMGB1 could be a therapeutic approach against the pathogenesis of viral infection.

Many studies have demonstrated that intracellular and extracellular HMGB1 play different roles in virus replication. For example, intracellular HMGB1 facilitates influenza virus and hepatitis C virus replication by directly interacting with viral RNA or nucleoprotein ^40,41. Vice versa, intracellular HMGB1 limits HIV replication by downregulating the long terminal repeat (LTR)-mediated transcription ⁴². Extracellular HMGB1 has also been reported to promote HIV replication in monocytic cells but decreases viral replication in primary macrophages ⁴³. Moreover, the antiviral effect of extracellular HMGB1 against hepatitis C virus has been established by the activation of the interferon signaling in virus-infected human hepatoma cell line ⁴⁴. Although HMGB1 has been found to have significant effects on various virus replication, the role of HMGB1 in ZIKV infection remains largely unknown.

This study revealed that dexamethasone treatment decreased both extracellular HMGB1 release and ZIKV replication. Dexamethasone has been shown to inhibit HMGB1 nuclear-to-cytoplasmic translocation via acetyltransferase attenuation, hence reducing the HMGB1-TLR4 inflammatory pathway ²¹. Moreover, dexamethasone's anti-inflammatory action, which reduces TNF-a, IFN-a, and IL-10 production, has also been demonstrated to reduce dengue virus replication ²⁴. Therefore, the inhibition of ZIKV replication by dexamethasone treatment was likely through the prevention of HMGB1 extracellular release.

To further investigate the role of intracellular HMGB1 in the antiviral mechanism of dexamethasone against ZIKV infection, HMGB1-depleted cells were used. This study showed no antiviral effects in dexamethasone-treated HMGB1-knockdown cells, signifying that the presence of intracellular HMGB1 is critical for the dexamethasone's antiviral activity. This finding is consistent with several earlier studies which demonstrated that HMGB1 retained in the nucleus plays a role in the antiviral response against dengue virus ⁴⁵, duck reovirus, duck Tembusu, duck plague virus ⁴⁶ and human immunodeficiency virus ⁴². In addition, the role of nuclear HMBG1 retention in upregulating interferon-stimulated genes (ISGs) expression to antagonise virus replication has been reported ^45,47. Thus, the anti-ZIKV mechanism of dexamethasone is most likely through preventing HMGB1 translocation, which results in HMGB1 retention in the cells. In conclusion, current findings suggest that ZIKV infection triggers HMGB1 translocation from the nucleus to cytoplasm and extracellular release in a time- and MOI-dependent manner. The findings of this study provide a better insight into the underlying anti-ZIKV mechanisms by dexamethasone, particularly through the regulation of HMGB1. Further in vivo investigation could provide better understanding of HMGB1’s role in ZIKV infection.

Cell culture and virus. Human hepatocellular carcinoma cells (Huh7, JCRB 0403) were cultured in Roswell Park Memorial Institute 1640 medium (RPMI; RBRC-RCB1942), enriched with 10% of heat-inactivated fetal bovine serum (FBS; Bovogen, Australia) and L-glutamine (Gibco, NY, USA). Huh7 cells were incubated at 37°C in a humidified incubator with 5% CO₂. Asian Zika virus (ZIKV) strain P6-740 (from Malaysia) was used in this study. ZIKV was archived in Tropical Infectious Diseases Research & Education Centre (TIDREC) at University of Malaya, Kuala Lumpur, Malaysia. African Green monkey kidney cells (Vero, ATCC- CCL81) in Dulbecco’s Modified Eagle Medium (DMEM; Gibco, NY, USA) were used for virus propagation and titration.

Virus infection and virus titer determination. Huh7 cells were infected with ZIKV at various MOIs, with and without dexamethasone (Sigma-Aldrich, St. Louis, MO, USA) added to cells at different concentrations. The cell culture supernatants were then collected at different time points (e.g., 24 h, 48 h and 72 h) for ZIKV titer determination using the focus-forming assay and expressed as Focus-Forming-Unit per ml (FFU/ml). The assay was carried out as previously reported ²⁵.

Enzyme-linked immunosorbent assay (ELISA). The amount of extracellular HMGB1 in cell culture supernatant was quantified using a commercially available human HMGB1 ELISA kit (Cloud-Clone Corp, USA; cat. SEA399Hu 96 tests) according to the manufacturer’s instructions.

Immunoblot assay. Huh7 cells were harvested at 24, 48 and 72h after ZIKV infection. Proteins were extracted from Huh7 cells as directed by the manufacturer using the NE-PER cytoplasmic and nuclear protein extraction kit (Thermo Scientific Pierce, Rockford, IL, USA). Micro BCA Protein Assay Kit (Thermo Scientific Pierce, Rockford, IL, USA) was used to quantify the protein concentration of each sample. Equal amounts of proteins were denatured with sodium dodecyl sulphate–sample loading buffer, separated using sodium dodecyl sulphate-polyacrylamide gel electrophoresis, and transferred to a polyvinylidene fluoride membrane for 14 minutes by the Bio-Rad semi-dry transfer system (Hercules, CA). Afterward, the membranes were blocked with 3% skimmed milk in PBS for 1 h at room temperature before being incubated with primary antibodies overnight at 4°C. The primary antibodies used in this study were as follows: rabbit anti-HMGB1 antibody (ab79823; 1: 1:10000–1:50000 dilution; Abcam, Cambridge, UK), rabbit anti-GADPH antibody (ab9485, 1:2500; Abcam, Cambridge, UK) and rabbit anti-PARP1 antibody (PLA0184, 1:2000-1:10000 dilution, Sigma-Aldrich, St. Louis, MO, USA). Blots were then incubated for 1 h at room temperature with a secondary goat anti-rabbit IgG antibody conjugated with horseradish peroxidase (HRP) (65-6120, 1:3,000–1:10,000; Invitrogen, Carlsbad, CA, USA). The chemiluminescence Western blotting kit (BioRad, Hercules, CA) was used to detect the presence of proteins.

HMGB1 gene knockdown in Huh7 cells. The shRNA approach was used to achieve stable knockdown of HMGB1 gene expression (shHMGB1) ⁴⁸. The recombinant lentiviruses carrying shRNA plasmid targeting human HMGB1 gene were purchased from OriGene Technologies (TL316576V, Rockville, MD, USA). A 50 percent confluent Huh7 cell monolayer was infected with the recombinant lentiviruses at a MOI of 20 in the presence of 8 µg/ml of polybrene, which was then incubated at 37°C overnight. After 24 hours, the culture medium was changed to a puromycin-containing selective medium with a final concentration of 1 µg/ml (Sigma-Aldrich, St. Louis, MO).

Statistical analysis. The statistically significant differences between the cell groups were determined by employing a one-way analysis of variance (ANOVA) and Bonferroni's multiple-comparison test with a 95 percent confidence interval (C.I.) to determine the significance of the variance. Graph-Pad Prism 8 was used to perform all statistical tests. The statistical significances of the groups were as follows: *P < 0.05, **P < 0.01, ***P < 0.001.

Acknowledgements

This study was supported in parts by the Ministry of Education Malaysia under the Higher Institution Centre of Excellence (HICoE) Program (Project MO002-2019), the Long Term Research Grant Scheme (LRGS MRUN Phase 1: LRGS MRUN/F1/01/2018) and the Fundamental Research Grant Scheme (FRGS FP015-2019A).

Author Contributions

K.L.C., N.Z., S.A.B. and S.S.S. involved in the study and experimental design. K.L.C and N.Z. conducted the experiments and analysed the results. K.L.C., N.Z., S.A.B., S.S.S., P.H. and R.L. wrote, reviewed and edited the manuscript. All the authors have reviewed the manuscript.

Additional Information

Competing interests: The authors declare no competing interests.

Sikka, V. et al. The emergence of Zika virus as a global health security threat: a review and a consensus statement of the INDUSEM Joint Working Group (JWG). Journal of global infectious diseases, 8, 3 (2016).
Lanciotti, R. S., Lambert, A. J., Holodniy, M., Saavedra, S. & Signor, L. d. C. C. Phylogeny of Zika virus in western hemisphere, 2015. Emerging infectious diseases, 22, 933 (2016).
Schuler-Faccini, L. Possible Association Between Zika Virus Infection and Microcephaly—Brazil, 2015.MMWR. Morbidity and Mortality Weekly Report65 (2016).
Dominguez-Moreno, R. et al. Mortality associated with a diagnosis of Guillain-Barré syndrome in adults of Mexican health institutions. Revista de neurologia, 58, 4–10 (2014).
Lange, S. S., Mitchell, D. L. & Vasquez, K. M. High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage. Proceedings of the National Academy of Sciences 105, 10320–10325(2008).
Yang, H., Wang, H., Czura, C. J. & Tracey, K. J. The cytokine activity of HMGB1. Journal of leukocyte biology, 78, 1–8 (2005).
Barqasho, B., Nowak, P., Abdurahman, S., Walther-Jallow, L. & Sönnerborg, A. Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro. Journal of General Virology, 91, 1800–1809 (2010).
Jung, J. H. et al. Hepatitis C virus infection is blocked by HMGB1 released from virus-infected cells. Journal of virology, JVI. 00682 – 00611(2011).
Kamau, E. et al. Dengue virus infection promotes translocation of high mobility group box 1 protein from the nucleus to the cytosol in dendritic cells, upregulates cytokine production and modulates virus replication. Journal of General Virology, 90, 1827–1835 (2009).
Gougeon, M., Melki, M. & Saidi, H. HMGB1, an alarmin promoting HIV dissemination and latency in dendritic cells. Cell death and differentiation, 19, 96 (2012).
Chu, J. & Ng, M. The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. Journal of General Virology, 84, 3305–3314 (2003).
Borde, C. et al. Stepwise release of biologically active HMGB1 during HSV-2 infection. PloS one, 6, e16145 (2011).
Chen, R. et al. HMGB1 as a potential biomarker and therapeutic target for severe COVID-19. Heliyon, 6, e05672 (2020).
Liu, Y. et al. Hepatitis B virus X protein stabilizes amplified in breast cancer 1 protein and cooperates with it to promote human hepatocellular carcinoma cell invasiveness., 56, 1015–1024 (2012).
Allonso, D. et al. Elevated serum levels of high mobility group box 1 (HMGB1) protein in dengue-infected patients are associated with disease symptoms and secondary infection. Journal of Clinical Virology, 55, 214–219 (2012).
Rashid, M. et al. Zika virus dysregulates human Sertoli cell proteins involved in spermatogenesis with little effect on tight junctions. PLoS neglected tropical diseases, 14, e0008335 (2020).
Fares-Gusmao, R. et al. Differential pattern of soluble immune markers in asymptomatic dengue, West Nile and Zika Virus Infections. Scientific reports, 9, 1–12 (2019).
Xu, L., Bao, H., Si, Y. & Wang, X. Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice. Inflamm. Res, 62, 507–514 (2013).
Zhao, S. et al. Dexamethasone inhibits NF–кBp65 and HMGB1 expression in the pancreas of rats with severe acute pancreatitis. Molecular medicine reports, 18, 5345–5352 (2018).
Liu, X. et al. Paeonol attenuates acute lung injury by inhibiting HMGB1 in lipopolysaccharide-induced shock rats. International immunopharmacology, 61, 169–177 (2018).
Zhang, J. et al. HMGB1-TLR4 signaling participates in renal ischemia reperfusion injury and could be attenuated by dexamethasone-mediated inhibition of the ERK/NF-κB pathway. American journal of translational research, 8, 4054 (2016).
Lee, J. S., Kim, S. R., Song, J. H., Lee, Y. P. & Ko, H. J. Anti-Human Rhinovirus 1B Activity of Dexamethasone viaGCR-Dependent Autophagy Activation. Osong public health and research perspectives, 9, 334 (2018).
Ilott, M., Salt, J., Gaskell, R. & Kitching, R. Dexamethasone inhibits virus production and the secretory IgA response in oesophageal–pharyngeal fluid in cattle persistently infected with foot-and-mouth disease virus. Epidemiology & Infection, 118, 181–187 (1997).
Reis, S. R. N. I. et al. An in vitro model for dengue virus infection that exhibits human monocyte infection, multiple cytokine production and dexamethasone immunomodulation. Memorias do Instituto Oswaldo Cruz, 102, 983–990 (2007).
Teoh, B. T. et al. Dengue virus type 1 clade replacement in recurring homotypic outbreaks. BMC evolutionary biology, 13, 1–10 (2013).
Andersson, U., Erlandsson-Harris, H., Yang, H. & Tracey, K. J. HMGB1 as a DNA‐binding cytokine. Journal of leukocyte biology, 72, 1084–1091 (2002).
Kuehl, L., Salmond, B. & Tran, L. Concentrations of high-mobility-group proteins in the nucleus and cytoplasm of several rat tissues. The Journal of cell biology, 99, 648–654 (1984).
Tang, D. et al. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells., 29, 5299–5310 (2010).
Ito, I., Fukazawa, J. & Yoshida, M. Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils. Journal of Biological Chemistry, 282, 16336–16344 (2007).
Ong, S. P., Lee, L. M., Leong, Y. F. I., Ng, M. L. & Chu, J. J. H. Dengue virus infection mediates HMGB1 release from monocytes involving PCAF acetylase complex and induces vascular leakage in endothelial cells. PloS one, 7, e41932 (2012).
Hosakote, Y. M., Brasier, A. R., Casola, A., Garofalo, R. P. & Kurosky, A. Respiratory syncytial virus infection triggers epithelial HMGB1 release as a damage-associated molecular pattern promoting a monocytic inflammatory response. Journal of virology, 90, 9618–9631 (2016).
Sun, R. et al. PCV2 induces reactive oxygen species to promote nucleocytoplasmic translocation of the viral DNA binding protein HMGB1 to enhance its replication.Journal of virology94,e00238-00220.
Wang, W. K. et al. Slower rates of clearance of viral load and virus-containing immune complexes in patients with dengue hemorrhagic fever. Clin. Infect. Dis, 43, 1023–1030 (2006).
Lotze, M. T. & Tracey, K. J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Reviews Immunology, 5, 331–342 (2005).
Qu, Y. et al. Newcastle disease virus infection triggers HMGB1 release to promote the inflammatory response., 525, 19–31 (2018).
Duan, E. et al. Porcine reproductive and respiratory syndrome virus infection triggers HMGB1 release to promote inflammatory cytokine production., 468, 1–9 (2014).
Chen, S. et al. Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer letters, 394, 22–32 (2017).
de Carvalho, G. C. et al. RAGE and CCR7 mediate the transmigration of Zika-infected monocytes through the blood-brain barrier., 224, 792–803 (2019).
Zou, S. S. et al. Brain Microvascular Endothelial Cells-Derived HMGB1 Facilitates Monocyte Transendothelial Migration Favoring JEV Neuroinvasion(2020).
Moisy, D. et al. HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication. Journal of virology, 86, 9122–9133 (2012).
Yu, R. et al. HMGB1 promotes hepatitis C virus replication by interaction with stem-loop 4 in the viral 5′ untranslated region. Journal of virology, 90, 2332–2344 (2015).
Naghavi, M. H. et al. Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter-and cell-specific manner., 314, 179–189 (2003).
Nowak, P. et al. HMGB1 activates replication of latent HIV-1 in a monocytic cell-line, but inhibits HIV-1 replication in primary macrophages., 34, 17–23 (2006).
Jung, J. H. et al. Hepatitis C virus infection is blocked by HMGB1 released from virus-infected cells. Journal of virology, 85, 9359–9368 (2011).
Zainal, N. et al. Resveratrol treatment reveals a novel role for HMGB1 in regulation of the type 1 interferon response in dengue virus infection. Scientific reports, 7, 1–12 (2017).
Hou, X. et al. High-mobility group box 1 protein (HMGB1) from Cherry Valley duck mediates signaling pathways and antiviral activity. Veterinary research, 51, 1–15 (2020).
Ma, C., Wang, Y., Dong, L., Li, M. & Cai, W. Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways. Acta biochimica et biophysica Sinica, 47, 207–213 (2015).
Hashemi, M., Zali, A., Hashemi, J., Oraee-Yazdani, S. & Akbari, A. Down-regulation of 14-3-3 zeta sensitizes human glioblastoma cells to apoptosis induction., 23, 616–625 (2018).

No competing interests reported.

Download PDF

Editorial decision: Major revision
03 Nov, 2021
Reviews received at journal
17 Oct, 2021
Reviewers agreed at journal
03 Oct, 2021
Reviewers invited by journal
03 Oct, 2021
Editor assigned by journal
29 Sep, 2021
Editor invited by journal
29 Sep, 2021
Submission checks completed at journal
29 Sep, 2021
First submitted to journal
23 Sep, 2021

You are reading this latest preprint version

High Mobility Group Box 1: a Novel Host Restriction Factor in Zika Virus Replication

Status:

Version 1

Abstract

Figures

Introduction

Results

Discussion

Methods

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1