Brain Microvascular Endothelial Cells-Derived HMGB1 Facilitates Monocyte Transendothelial Migration Favoring JEV Neuroinvasion

Zou, Song-Song; Zou, Qing-Cui; Xiong, Wenjing; Cui, Ning-Yi; Wang, Ke; Liu, Haoxuan; Lou, Wen-Juan; Higazy, Doaa; Chen, Haowei; Zhang, Yage; Cui, Min

doi:10.21203/rs.3.rs-108411/v1

Cited by 3 publications

(1 citation statement)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Chin¹,

Zainal²,

Sam³

et al. 2021

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Chin¹,

Zainal²,

Sam³

et al. 2021

Preprint

View full text Add to dashboard Cite

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Intracellular translocation of HMGB1 is important for Zika virus replication in Huh7 cells

Chin

Zainal

Sam

et al. 2022

Sci Rep

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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, and HMGB1-knockdown (shHMGB1) Huh7 cells. 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 72-h post-infection (h.p.i). The extracellular HMGB1 level was elevated in a time- and multiplicity of infection (MOI)-dependent manner. Treatment of the ZIKV-infected cells with dexamethasone (150 µM) 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, were not observed in the dexamethasone-treated shHMGB1 cells. These results suggest that translocation of HMGB1 occurred during ZIKV infection and inhibition of the translocation by dexamethasone coincided with a reduction in ZIKV replication. These findings highlight the potential of targeting the localization of HMGB1 in affecting ZIKV infection.

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Resveratrol Treatment-induced Nuclear HMGB1 Retention is Critical for Inducing Host Interferon Responses Against Zika Virus

AbuBakar

Chin

Zainal

et al. 2023

NPJ

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Background: Zika virus (ZIKV) infection is a public health concern and currently there is no specific therapeutic or approved vaccine. Resveratrol (RESV), a natural antiviral compound, has been shown to possess antiviral properties against ZIKV and other viral infections, but the mechanisms of action against ZIKV remain unknown. Objective: This study aimed to investigate the role of the high mobility group box 1 protein (HMGB1) in the underlying anti-ZIKV mechanisms of RESV. Methods: HMGB1 protein expression and ZIKV replication in both the RESV-treated wild-type (WT) and HMGB1-knockdown (shHMGB1) Huh7 cells were analyzed using ELISA, immunofluorescence assay, immunoblot assay, focus-forming assay and qRT-PCR. HMGB1’s role was explored by evaluating the changes in the type-1 interferon (IFN) response genes using the qRT-PCR and immunoblot assays. Results: The treatment of the ZIKV-infected WT Huh7 cells with RESV significantly reduced ZIKV titers by >90% (P < 0.001) at 48 and 72 hr pi in a dose-dependent manner and inhibited ZIKV-induced HMGB1 translocation (P < 0.001), resulting in nuclear HMGB1 accumulation. Compared to the WT Huh7 cells and shHMGB1 Huh7 cells without RESV treatment showed a significant increase in the infectious virus titers and RNA with a maximum rise of 74% (P < 0.001) and 65% (P < 0.01), respectively. RESV treatment of the ZIKV-infected WT Huh7 cells significantly increased the MxA (one of the classical interferon-stimulated genes, ISGs) and IFN-β levels (p < 0.05). The treatment of the infected shHMGB1 Huh7 cells with RESV showed a less effective antiviral response (P > 0.05) and did not cause changes in the expressions of MxA and IFN-β. Conclusion: RESV possesses therapeutic activity against ZIKV infection and the mechanism of action is mainly attributed to HMGB1 nuclear retention, which could upregulate the type-1 IFN and ISGs. other: -

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Brain Microvascular Endothelial Cells-Derived HMGB1 Facilitates Monocyte Transendothelial Migration Favoring JEV Neuroinvasion

Cited by 3 publications

References 64 publications

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

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

Intracellular translocation of HMGB1 is important for Zika virus replication in Huh7 cells

Resveratrol Treatment-induced Nuclear HMGB1 Retention is Critical for Inducing Host Interferon Responses Against Zika Virus

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