Virus-Induced Ca
            <sup>2+</sup>
            Influx Extends Survival of West Nile Virus-Infected Cells

Scherbik, Svetlana V.; Brinton, Margo A.

doi:10.1128/jvi.00144-10

Cited by 83 publications

(73 citation statements)

References 57 publications

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Section: Discussionmentioning

confidence: 99%

“…Calcium transport was previously shown to be required for efficient propagation of WNV (61). WNV infection was shown to lead to rapid and sustained Ca 2ϩ influx through Ca 2ϩ channels and endocytosis (61). Calcium transport depletion by specific inhibitors of Ca 2ϩ channels and the Ca 2ϩ -binding protein CB-D28k were shown to have a strong inhibitory effect on WNV replication (61,62).…”

Section: Discussionmentioning

confidence: 99%

“…WNV infection was shown to lead to rapid and sustained Ca 2ϩ influx through Ca 2ϩ channels and endocytosis (61). Calcium transport depletion by specific inhibitors of Ca 2ϩ channels and the Ca 2ϩ -binding protein CB-D28k were shown to have a strong inhibitory effect on WNV replication (61,62). Ca 2ϩ influx is thought to be required for early stages of virus replication (possibly for virus-induced rearrangement of the endoplasmic reticulum membrane) and for later infection stages, when Ca 2ϩ -dependent activation of caspase 3 cleavage leads to decreased activation of the FAK and ERK1/2 pathways, extending the survival of WNV-infected cells (62).…”

Section: Discussionmentioning

confidence: 99%

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Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

Slonchak

Shannon

Pali

et al. 2016

J Virol

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West Nile virus (WNV) is a mosquito-transmitted flavivirus that naturally circulates between mosquitos and birds but can also infect humans, causing severe neurological disease. The early host response to WNV infection in vertebrates primarily relies on the type I interferon pathway; however, recent studies suggest that microRNAs (miRNAs) may also play a notable role. In this study, we assessed the role of host miRNAs in response to WNV infection in human cells. We employed small RNA sequencing (RNA-seq) analysis to determine changes in the expression of host miRNAs in HEK293 cells infected with an Australian strain of WNV, Kunjin (WNV KUN ), and identified a number of host miRNAs differentially expressed in response to infection. Three of these miRNAs were confirmed to be significantly upregulated in infected cells by quantitative reverse transcription (qRT)-PCR and Northern blot analyses, and one of them, miR-532-5p, exhibited a significant antiviral effect against WNV KUN infection. We have demonstrated that miR-532-5p targets and downregulates expression of the host genes SESTD1 and TAB3 in human cells. Small interfering RNA (siRNA) depletion studies showed that both SESTD1 and TAB3 were required for efficient WNV KUN replication. We also demonstrated upregulation of mir-532-5p expression and a corresponding decrease in the expression of its targets, SESTD1 and TAB3, in the brains of WNV KUN -infected mice. Our results show that upregulation of miR-532-5p and subsequent suppression of the SESTD1 and TAB3 genes represent a host antiviral response aimed at limiting WNV KUN infection and highlight the important role of miRNAs in controlling RNA virus infections in mammalian hosts. IMPORTANCEWest Nile virus (WNV) is a significant viral pathogen that poses a considerable threat to human health across the globe. There is no specific treatment or licensed vaccine available for WNV, and deeper insight into how the virus interacts with the host is required to facilitate their development. In this study, we addressed the role of host microRNAs (miRNAs) in antiviral response to WNV in human cells. We identified miR-532-5p as a novel antiviral miRNA and showed that it is upregulated in response to WNV infection and suppresses the expression of the host genes TAB3 and SESTD1 required for WNV replication. Our results show that upregulation of miR-532-5p and subsequent suppression of the SESTD1 and TAB3 genes represent an antiviral response aimed at limiting WNV infection and highlight the important role of miRNAs in controlling virus infections in mammalian hosts. W est Nile virus (WNV) is a mosquito-transmitted flavivirus associated with outbreaks of encephalitis in humans and horses around the world (1). The most significant WNV outbreaks have occurred in North America, where a highly pathogenic strain of WNV emerged in New York in 1999. This strain rapidly spread to all the states and by 2011 had infected an estimated 1.8 million people, causing close to 360,000 illnesses and ϳ1,300 deaths (2). The majority of ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

Slonchak

Shannon

Pali

et al. 2016

J Virol

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“…As mentioned above, the kinetics of virus-induced survival signaling varies among cell lines and flaviviruses, and as a consequence, the extent of apoptosis is affected. With regard to WNV, Scherbik and Brinton (28) reported that infection of MEFs significantly increases phospho-Akt within 2 h of infection and this effect is sustained for more than 24 h. Similarly, JEV infection of RBA-1 cells activates the PI3K/Akt pathway, resulting in stimulatory phosphorylation of Akt within minutes (49). In contrast, WNV infection of neuro2A cells, a mouse neuroblastoma cell line, results in extensive cell death in less than 72 h, even at very low MOIs (50).…”

Section: Discussionmentioning

confidence: 99%

“…However, unlike Sindbis virus and VSV, replication of WNV and other flaviviruses is relatively slow, and therefore, it is not seemingly beneficial to the virus if the first viral protein produced in an infected cell induces programmed cell death. In contrast, during the early stages of flavivirus infection, apoptosis appears to be inhibited by a process that involves activation of the prosurvival kinase Akt (26)(27)(28). In cells infected with WNV, DENV, or JEV, elevated Akt activity can be detected within an hour.…”

mentioning

confidence: 99%

The West Nile Virus Capsid Protein Blocks Apoptosis through a Phosphatidylinositol 3-Kinase-Dependent Mechanism

Urbanowski

Hobman

2013

J Virol

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West Nile virus (WNV) is a mosquito-transmitted pathogen that can cause serious disease in humans. Our laboratories are focused on understanding how interactions between WNV proteins and host cells contribute to virus replication and pathogenesis. WNV replication is relatively slow, and on the basis of earlier studies, the virus appears to activate survival pathways that delay host cell death during virus replication. The WNV capsid is the first viral protein produced in infected cells; however, its role in virus assembly is not required until after replication of the genomic RNA. Accordingly, from a temporal perspective, it is perfectly suited to block host cell apoptosis during virus replication. In the present study, we provide evidence that the WNV capsid protein blocks apoptosis through a phosphatidylinositol (PI) 3-kinase-dependent pathway. Specifically, expression of this protein in the absence of other viral proteins increases the levels of phosphorylated Akt, a prosurvival kinase that blocks apoptosis through multiple mechanisms. Treatment of cells with the PI 3-kinase inhibitor LY294002 abrogates the protective effects of the WNV capsid protein.

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The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca²⁺‐LRMDA Axis in Myeloid Cells

Guo

Gao

et al. 2022

Advanced Science

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The transient receptor potential vanilloid 2 (TRPV2) channel is a nonselective cation channel that has been implicated in multiple sensory processes in the nervous system. Here, it is shown that TRPV2 in myeloid cells facilitates virus penetration by promoting the tension and mobility of cell membrane through the Ca 2+ -LRMDA axis. Knockout of TRPV2 in myeloid cells or inhibition of TRPV2 channel activity suppresses viral infection and protects mice from herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection. Reconstitution of TRPV2 but not the Ca 2+ -impermeable mutant TRPV2 E572Q into LyZ2-Cre;Trpv2 fl/fl bone marrow-derived dendritic cells (BMDCs) restores viral infection. Mechanistically, knockout of TRPV2 in myeloid cells inhibits the tension and mobility of cell membrane and the penetration of viruses, which is restored by reconstitution of TRPV2 but not TRPV2 E572Q . In addition, knockout of TRPV2 leads to downregulation of Lrmda in BMDCs and BMDMs, and knockdown of Lrmda significantly downregulates the mobility and tension of cell membrane and inhibits viral infections in Trpv2 fl/fl but not LyZ2-Cre;Trpv2 fl/fl BMDCs. Consistently, complement of LRMDA into LyZ2-Cre;Trpv2 fl/fl BMDCs partially restores the tension and mobility of cell membrane and promotes viral penetration and infection. These findings characterize a previously unknown function of myeloid TRPV2 in facilitating viral infection though the Ca2 + -LRMDA axis.

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Virus-Induced Ca ²⁺ Influx Extends Survival of West Nile Virus-Infected Cells

Cited by 83 publications

References 57 publications

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

The West Nile Virus Capsid Protein Blocks Apoptosis through a Phosphatidylinositol 3-Kinase-Dependent Mechanism

The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca²⁺‐LRMDA Axis in Myeloid Cells

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Virus-Induced Ca 2+ Influx Extends Survival of West Nile Virus-Infected Cells

Cited by 83 publications

References 57 publications

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

The West Nile Virus Capsid Protein Blocks Apoptosis through a Phosphatidylinositol 3-Kinase-Dependent Mechanism

The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca2+‐LRMDA Axis in Myeloid Cells

Contact Info

Product

Resources

About

Virus-Induced Ca ²⁺ Influx Extends Survival of West Nile Virus-Infected Cells

The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca²⁺‐LRMDA Axis in Myeloid Cells