HSV-2 disrupts gap junctional intercellular communication between mammalian cells in vitro

Fischer, Nicholas O.; Mbuy, Gustave K.N.; Woodruff, Richard I.

doi:10.1016/s0166-0934(00)00260-3

Cited by 25 publications

(15 citation statements)

References 37 publications

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“…Indeed, we found that cells deficient in gap junctions produced significantly less IFN␤ and TNF␣, resulting in substantial decreases in expression of antiviral genes such as PKR. Furthermore, 2 dsDNA viruses that represent important causes of human disease, herpesvirus HSV2 and human papilloma virus HPV16, were shown to express viral proteins that close gap junctions of infected cells, suggesting that viruses have identified gap junction communication as a critical mode for host defense signaling and have begun evolving strategies to inhibit these defenses (27,28).…”

Section: Discussionmentioning

confidence: 99%

DNA-triggered innate immune responses are propagated by gap junction communication

Patel

King

Casali

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cells respond to infection by sensing pathogens and communicating danger signals to noninfected neighbors; however, little is known about this complex spatiotemporal process. Here we show that activation of the innate immune system by double-stranded DNA (dsDNA) triggers intercellular communication through a gap junctiondependent signaling pathway, recruiting colonies of cells to collectively secrete antiviral and inflammatory cytokines for the propagation of danger signals across the tissue at large. By using live-cell imaging of a stable IRF3-sensitive GFP reporter, we demonstrate that dsDNA sensing leads to multicellular colonies of IRF3-activated cells that express the majority of secreted cytokines, including IFN␤ and TNF␣. Inhibiting gap junctions decreases dsDNA-induced IRF3 activation, cytokine production, and the resulting tissue-wide antiviral state, indicating that this immune response propagation pathway lies upstream of the paracrine action of secreted cytokines and may represent a host-derived mechanism for evading viral antiinterferon strategies.innate immunity ͉ IRF ͉ TLR ͉ interferon

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Section: Discussionmentioning

confidence: 99%

DNA-triggered innate immune responses are propagated by gap junction communication

Patel

King

Casali

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Indirect evidence for the importance of gap junctions in immunity comes from the observation that viruses -such as herpes simplex virus (HSV) and human papillomavirus (HPV) -actively influence gap junction communication [25][26][27][28]. Compounds known to be involved in immune responses -such as peptidoglycan, lipopolysaccharide (LPS), tumor necrosis factors (TNF) and interferons (IFN) -can influence the expression of gap junctions [29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, transcription during latency of factors that cause downregulation of gap junctions might help to minimize the risk of detection. Although it is not known if such a mechanism would help latent viruses to evade immunosurveillance, it is interesting to note that HSV and HPV both undergo latency and have both been shown to downregulate gap junctions [25][26][27][28]. However, because many details of the latent phase and overall life cycle of both viruses are still not well-understood, the significance of this gap junction downregulation remains speculative.…”

Section: Introductionmentioning

confidence: 99%

Gap junction-mediated antigen transport in immune responses

Handel¹,

Yates²,

Pilyugin³

et al. 2007

Trends in Immunology

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“…Recent studies have shown electrophysiologically that down-regulation of gap junctions by herpes simplex virus-type 2 (HSV-2) begins before viral DNA replication, and long before morphological signs of infection (Fischer et al, 2001). In addition, Musee et al (2002) demonstrated that antiviral agents affect electrical coupling in HSV-2 infected cells in different ways, depending on the mechanism of action of the agent.…”

Section: ) Introductionmentioning

confidence: 99%

Herpes simplex virus-type 2 infectivity and agents that block gap junctional intercellular communication

et al. 2007

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SUMMARYIn rat liver epithelial (WB) cells, the protein kinase C inhibitor H7 blocked gap junctional intercellular communication (GJIC) and reduced virus infectivity. Octanol, 18-beta-glycyrrhetinic acid, and staurosporine, agents that reduce GJIC, had no effect upon virus infectivity. Previous studies demonstrated that herpes simplex virus-type 2 (HSV-2) infection was accompanied by attenuated GJIC. Of agents tested, only H7 reduced plaque forming unit (pfu) ability in a dose-dependent manner with 100% plaque reduction at 40 μM without evidence of cytotoxicity. Dye transfer indicated that H7 decreased GJIC, although Western blotting revealed that it did not alter phosphorylation of the gap junction protein, connexin 43 (Cx43). Using indirect immunofluorescence, Cx43 was found to localize in membrane plaques in uninfected cells and H-7 did not alter this distribution. However, Cx43 was lost from the membrane at 24 hrs in both H-7 treated and untreated cells infected with HSV-2. Viral infection increased serine phosphorylation, particularly in the nuclear region, and this effect was reduced following H-7 treatment. Thus, H-7 attenuated both GJIC and infectivity of HSV-2 in WB cells but the anti-viral effects were due to reduced nuclear protein phosphorylation rather than alterations in phosphorylation or localization of Cx43. KeywordsGap junctions; Connexin 43; protein kinase C; H7; HSV-2 1) INTRODUCTIONIt has long been known that certain RNA and tumor viruses decrease gap junctional communication among infected cells (Atkinson et al., 1981;Crow et al., 1990;Danave et al., 1994;Ennaji et al., 1995;Faccini et al., 1996, Jou et al., 1995. Recent studies have shown electrophysiologically that down-regulation of gap junctions by herpes simplex virus-type 2 (HSV-2) begins before viral DNA replication, and long before morphological signs of infection (Fischer et al., 2001). In addition, Musee et al. (2002) demonstrated that antiviral agents affect electrical coupling in HSV-2 infected cells in different ways, depending on the mechanism of action of the agent. However, it was not clear if GJIC down-regulation was initiated by the infected cells or by their surrounding uninfected neighbors. If the latter, drugs that reduce GJIC might protect neighboring cells from infection.* To whom all correspondence should be addressed: Phone -(610)-436-2985, Fax -(610)-436-2183, e-mail-mknabb@wcupa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. How HSV-2 induces gap junctional down-regulation is unknown although both viral-or cellmediated mechanisms are possible. Gap junction channels are...

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HSV-2 disrupts gap junctional intercellular communication between mammalian cells in vitro

Cited by 25 publications

References 37 publications

DNA-triggered innate immune responses are propagated by gap junction communication

DNA-triggered innate immune responses are propagated by gap junction communication

Gap junction-mediated antigen transport in immune responses

Herpes simplex virus-type 2 infectivity and agents that block gap junctional intercellular communication

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