Cellular Targets for the Treatment of Flavivirus Infections

Zakaria, Mohammad Khalid; Carletti, Tea; Marcello, Alessandro

doi:10.3389/fcimb.2018.00398

Cited by 49 publications

(53 citation statements)

References 101 publications

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“…Zika virus (ZIKV) is a mosquito-borne flavivirus that has recently been associated with severe consequences of infection including congenital microcephaly [1,2]. There remains no specific antiviral in clinical use for ZIKV, reflecting a need for a better understanding of the basic biology of this virus [3,4]. Flaviviruses encode only 10 proteins and rely on the manipulation of host cell processes to facilitate their replication cycle.…”

Section: Introductionmentioning

confidence: 99%

IRE1α Promotes Zika Virus Infection via XBP1

Kolpikova

Tronco

Hartigh

et al. 2020

Viruses

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Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1α, a component of the cellular response to ER stress. IRE1α is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1α initiates nonconventional cytoplasmic splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor, which upregulates ER-related targets. We find that ZIKV infection induces XBP1 mRNA splicing and induction of XBP1 target genes. Small molecule inhibitors of IRE1α, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1α. Optimal ZIKV RNA replication requires both IRE1α and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1α nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1α and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1α promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.proteins: protein kinase receptor-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 α (IRE1α). ER stress causes IRE1α to undergo oligomerization and autophosphorylation, which activates its cytosolic RNase domain to initiate nonconventional splicing of XBP1 mRNA. Spliced XBP1 is a specific product of activated IRE1α and encodes a transcription factor that upregulates targets that are involved in ER function [11]. IRE1α also targets other specific RNAs, leading to their degradation in a process termed regulated IRE1-dependent decay (RIDD) [12,13].The role of IRE1α in infection appears to vary for different members of the Flaviviridae family. Hepatitis C virus (HCV) activates IRE1α [14] to promote viral replication [15] independently of XBP1 by preventing apoptotic death of infected cells [16]. Dengue (DENV) and Japanese encephalitis viruses (JEV) also benefit from IRE1α via an XBP1-independent mechanism [17-20], whereas West Nile virus (WNV) replication is unaffected by either IRE1α [21,22] or XBP1 [23]. Conflicting results have been obtained for tick-borne encephalitis virus, with IRE1α nuclease inhibition either limiting viral replication [24] or having no effect [22]. ZIKV activates IRE1α, as demonstrated by the presence of spliced XBP1 in ZIKV-infected cultured cells and brain tissue from ZIKV-infected embryonic mice [25][26][27]. In this study, we examined the role of IRE1α in ZIKV infection and found that IRE1α promotes ZIKV replication via XBP1 in cultured cells. We further found that genetic disruption of IRE1α and XBP1 lim...

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Section: Introductionmentioning

confidence: 99%

IRE1α Promotes Zika Virus Infection via XBP1

Kolpikova

Tronco

Hartigh

et al. 2020

Viruses

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“…Flaviviruses share several common cellular factors in their infectious cycle that might specifically be targeted by benzavir-2 [1,13,44]. Our previous findings of the broad-spectrum antiviral activity for benzavir-2, inhibiting both DNA and RNA viruses, indicated that benzavir-2 could act on a host cell target(s).…”

Section: Discussionmentioning

confidence: 99%

“…However, up to date, there are no approved antiviral therapies for flaviviruses. Several preclinical and investigational drugs have been assessed for anti-flavivirus activity [11][12][13][14]. However, flaviviruses often escape antivirals that target specific viral proteins because of the high mutation rates [15].…”

Section: Introductionmentioning

confidence: 99%

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Antiviral Activity of Benzavir-2 against Emerging Flaviviruses

Gwon

Strand

Lindqvist

et al. 2020

Viruses

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Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA-and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC 50 value of 0.8 ± 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

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“…This upregulation was not significantly affected by addition of celgosivir, despite celgosivir reducing magnitude of ZIKV infection. Since the results of misfolded viral proteins includes not only reduced successful virus assembly and maturation but also protein accumulation in the ER and eventual ERAD, iminosugar treatment can induce ER stress and the unfolded protein response (Zakaria et al, 2018). Such a response can lead to stimulation of antiviral innate immune response pathways as well as apoptosis to limit viral infection (Smith, 2014).…”

Section: Discussionmentioning

confidence: 99%

Iminosugars With Endoplasmic Reticulum α-Glucosidase Inhibitor Activity Inhibit ZIKV Replication and Reverse Cytopathogenicity in vitro

et al. 2020

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Zika virus (ZIKV), a vector-borne virus of the family Flaviviridae, continues to spread and remains a significant global public health threat. Currently, there are no approved vaccines or antivirals against ZIKV. We investigated the anti-ZIKV ability of three iminosugars with endoplasmic reticulum α-glucosidase inhibitor (ER-AGI) activity, namely deoxynojirimycin (DNJ), castanospermine, and celgosivir. None of the three iminosugars showed any significant cytotoxicity in Vero or human microglia CHME3 cells when applied for 72 h at concentrations up to 100 µM. Iminosugar treatment of Vero or CHME3 cells prior to ZIKV infection resulted in significant inhibition of ZIKV replication over 48 h. Reduction in ZIKV replication in iminosugar-treated cells was not associated with any significant change in the expression levels of key antiviral genes. Following infection with three different strains of ZIKV, iminosugar-treated Vero or CHME3 cells showed no cell death, whereas vehicle-treated control cells exhibited 50-60% cell death at 72 h post-infection (hpi). While there was no significant difference in apoptosis between iminosugar-treated and control cells, iminosugar-treated cells exhibited a substantial reduction of necrosis at 72 hpi following ZIKV infection. In summary, iminosugars with ER-AGI activity inhibit ZIKV replication and significantly reduce necrosis without altering the antiviral gene expression and apoptosis of infected human cells. The results of this study strongly suggest that iminosugars are promising anti-ZIKV antiviral agents and such warrant further in vivo studies.

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Cellular Targets for the Treatment of Flavivirus Infections

Cited by 49 publications

References 101 publications

IRE1α Promotes Zika Virus Infection via XBP1

IRE1α Promotes Zika Virus Infection via XBP1

Antiviral Activity of Benzavir-2 against Emerging Flaviviruses

Iminosugars With Endoplasmic Reticulum α-Glucosidase Inhibitor Activity Inhibit ZIKV Replication and Reverse Cytopathogenicity in vitro

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