Induction of IL-6 in Transcriptional Networks in Corneal Epithelial Cells after Herpes Simplex Virus Type 1 Infection

Terasaka, Yuki; Miyazaki, Dai; Yakura, Keiko; Haruki, Tomoko; Inoue, Yoshitsugu

doi:10.1167/iovs.09-4624

Cited by 31 publications

(36 citation statements)

References 50 publications

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“…Both NF-kB and IE proteins stimulate IL-6 production, 83,89,90 and an IL-6erelated pathway up-regulates GADD45b in herpes simplex virus-1einfected corneal epithelial cells. 91 …”

Section: Discussionmentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from midgestation placentas formed foci of infection, and interferon-b production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-x L by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-x L , indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment. (Am J Pathol 2016 http://dx

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“…Both NF-kB and IE proteins stimulate IL-6 production, 83,89,90 and an IL-6erelated pathway up-regulates GADD45b in herpes simplex virus-1einfected corneal epithelial cells. 91 …”

Section: Discussionmentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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“…Of the factors evaluated, only IGF-2, IL-6, IL-1␤, PDGF, and ANGPT2 transcripts were elevated in the TNF-␣ Ϫ/Ϫ mouse corneas compared to the WT group (Table 1). A previous bioinformatics-based analysis of global transcriptional responses in corneal epithelial cells following HSV-1 infection revealed a critical role for IL-6 in the expression of over 20 cytokines, including PDGF, IL-8, and VEGFA, suggesting that IL-6 may directly or indirectly influence angiogenesis (15). To determine if IL-6 was compensating for the loss of TNF-␣ in our model, HSV-1-infected TNF-␣ Ϫ/Ϫ mice were treated with neutralizing IL-6 Ab and evaluated for corneal lymphangiogenesis.…”

Section: Fig 2 Neutralization Of Tnf-␣ Impairs Hsv-1-induced Corneal mentioning

confidence: 99%

Tumor Necrosis Factor Alpha and Interleukin-6 Facilitate Corneal Lymphangiogenesis in Response to Herpes Simplex Virus 1 Infection

Bryant-Hudson

Gurung

Zheng

et al. 2014

J Virol

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Herpes simplex virus 1 (HSV-1) is a common human pathogen of clinical significance due to its association with vision impairment and encephalitis. In a mouse model of ocular neovascularization, we have previously shown that HSV-1 elicits the genesis of lymphatic vessels into the cornea proper through epithelial cell expression of vascular endothelial growth factor A (VEGFA) dependent upon expression of VEGFR2 during acute infection. We hypothesized that other factors may be involved in lymphangiogenesis, with proinflammatory cytokines as the leading candidates. IMPORTANCEWe have identified at least two proinflammatory cytokines expressed locally that are involved in the genesis of lymphatic vessels in the normally avascular cornea in response to HSV-1 infection. This finding provides the basis to target IL-6 and TNF-␣ as additional proangiogenic factors in the cornea during the development of herpetic stromal keratitis as a means to alleviate further neovascularization and tissue pathology associated with the host immune response to the pathogen.

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“…HSV-1 productively infects epithelial cells and establishes latent infection in sensory ganglia for the life of the host (Kumaraguru & Rouse, 2002;Terasaka et al, 2010). Currently, no cure exists against HSV-1, which can be transmitted via asymptomatic shedding by latently infected individuals (Hill & Clement, 2009).…”

Section: Introductionmentioning

confidence: 99%

Syndecan-1 and syndecan-2 play key roles in herpes simplex virus type-1 infection

Bacsa

Karasneh

Dósa

et al. 2010

Journal of General Virology

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Herpes simplex virus type 1 (HSV-1) is an important human pathogen and a leading cause of infectious blindness in the developed world. HSV-1 exploits heparan sulfate proteoglycans (HSPG) for attachment to cells. While the significance of heparan sulphate (HS) moieties in HSV-1 infection is well established, the role of specific proteoglycan core proteins in the infection process remains poorly understood. The objective of this study was to assess the roles of syndecan-1 and syndecan-2 core proteins in HSV-1 infection, both of which are expressed by many HSV-1 target cell types. Our results demonstrate that syndecan-1 and syndecan-2 gene silencing by RNA interference reduces HSV-1 entry, plaque formation and facilitates cell survival. Furthermore, HSV-1 infection increases syndecan-1 and syndecan-2 protein synthesis and a resultant increase in cell surface expression of HS. Our observations suggest that changes in syndecan-1 and syndecan-2 expression levels may be related to active viral infection. Taken together, our findings provide new insights into HSPG functions during HSV-1 entry and spread. INTRODUCTIONHerpes simplex virus type 1 (HSV-1) is a clinically important pathogen and a leading cause of infectious blindness in the developed world. HSV-1 productively infects epithelial cells and establishes latent infection in sensory ganglia for the life of the host (Kumaraguru & Rouse, 2002;Terasaka et al., 2010). Currently, no cure exists against HSV-1, which can be transmitted via asymptomatic shedding by latently infected individuals (Hill & Clement, 2009). Prevention of virus transmission to uninfected people is a real challenge compounded by our limited understanding of HSV-1-host cell interactions including virus entry, which is the first essential step for the establishment of an acute and/or latent infection.Enveloped viruses including HSV-1 penetrate host cells by inducing fusion between the virus envelope and the host cell membrane. HSV-1 entry is a stepwise process, which starts when HSV-1 envelope glycoproteins gB and gC attach to cell surface heparan sulfate proteoglycans (HSPGs) (Herold et al., 1991;Nicola et al., 2003;Trybala et al., 2000). This initial interaction enables HSV-1 glycoprotein D (gD) to bind to one of the known gD entry co-receptors. There are three classes of gD co-receptors that have been characterized: nectin-1 (HveC) and nectin-2 (HveB), which are both members of the immunoglobulin superfamily (Geraghty et al., 1998), herpesvirus entry mediator (HVEM) that belongs to the tumour necrosis factor receptor family (Montgomery et al., 1996), and 3-O-sulfated heparan sulfate (3-OS HS) which is a specifically modified form of heparan sulfate (HS) (Shukla et al., 1999b; O'Donnell et al., 2010). The binding of gD to one of its receptors leads to conformational changes in gD that allows it to activate a multiglycoprotein complex involving gB, gD, gH and gL that triggers the viral fusion with the host cell membrane (Atanasiu et al., 2007;Spear et al., 2000). This fusion mechanism is utilized...

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Induction of IL-6 in Transcriptional Networks in Corneal Epithelial Cells after Herpes Simplex Virus Type 1 Infection

Abstract: HCECs respond to HSV-1 infection by initiating mitogen-activated protein kinase-related transcriptional events, and IL-6 may serve to induce expression of an array of inflammatory mediators.

Cited by 31 publications

References 50 publications

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tumor Necrosis Factor Alpha and Interleukin-6 Facilitate Corneal Lymphangiogenesis in Response to Herpes Simplex Virus 1 Infection

Syndecan-1 and syndecan-2 play key roles in herpes simplex virus type-1 infection

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