Expression of Nectin-1 in Normal and Herpes Simplex Virus Type 1-Infected Murine Brain

Shukla, Deepak; Scanlan, P.M.; Tiwari, Vaibhav; Sheth, Veeral; Clément, Christian; Guzman-Hartman, Grace; Dermody, Terence S.; Vályi-Nagy, Tibor

doi:10.1097/00129039-200609000-00014

Cited by 19 publications

(13 citation statements)

References 46 publications

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“…Prior studies have demonstrated that the HSV-1 entry receptor nectin-1 is expressed throughout the adult brain, including the choroid plexus ( 17 ). Nectin-1 is sufficient for HSV binding and entry ( 18 ), so this suggests a differential susceptibility of the choroid plexus to HSV-1 based on innate host factors.…”

Section: Resultsmentioning

confidence: 99%

The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

Wilcox

Folmsbee

Muller

et al. 2016

mBio

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Newborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis.

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Section: Resultsmentioning

confidence: 99%

The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

Wilcox

Folmsbee

Muller

et al. 2016

mBio

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“…Herpes viral glycoproteins use other cell surface receptors for entry, the most common of which being nectin-1. However, it has been shown that expression of nectin-1 is diminished before cell death in neuronal cells of infected mice and human corneal epithelial cells during egress [ 25 – 26 ]. It is likely, though not well studied, that the surface expression of other HSV entry receptors is also diminished with infection.…”

Section: Discussionmentioning

confidence: 99%

Heparanase is a host enzyme required for herpes simplex virus-1 release from cells

et al. 2015

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Herpesviruses exemplified by herpes simplex virus-1 (HSV-1) attach to cell surface heparan sulfate (HS) for entry into host cells. However, during a productive infection the HS moieties on parent cells can trap newly exiting viral progenies and inhibit their release. Here, we demonstrate that a HS-degrading enzyme of the host, heparanase (HPSE), is upregulated through NF-kB and translocated to the cell surface upon HSV-1 infection for the removal of HS to facilitate viral release. We also find a significant increase in HPSE release in vivo during infection of murine corneas and that knockdown of HPSE in vivo inhibits virus shedding. Overall, we propose that HPSE acts as a molecular switch for turning a virus-permissive “attachment mode” of host cells to a virus-deterring “detachment mode”. Since many human viruses use HS as an attachment receptor, the HPSE-HS interplay may delineate a common mechanism for virus release.

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“…25,33,34 Nectin-1 is extensively expressed in human cells of epithelial and neuronal origin, while nectin-2 is widely expressed in many human tissues, but has limited expression in neuronal cells. 33,37 HVEM mediates entry of HSV-1 into T-lymphocytes and trabecular meshwork cells and HSV-2 entry into corneal fibroblasts. 35,38,39 HSV-1, but not HSV-2, entry is known to be mediated by 3- O S HS, which is expressed in many human cell lines.…”

Section: Introductionmentioning

confidence: 99%

Role of Nectin-1, HVEM, and PILR-α in HSV-2 Entry into Human Retinal Pigment Epithelial Cells

Shukla

Singh

Shukla

2009

Invest. Ophthalmol. Vis. Sci.

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Purpose Herpes simplex virus-type 2 (HSV-2) can cause Acute Retinal Necrosis (ARN), which can lead to exudative and rhegmatogenous retinal detachment; yet, little is know about the cellular and molecular mechanisms of HSV-2 entry into retinal pigment epithelial (RPE) cells. The goal of this study was to establish the identity of the critical receptors utilized by the virus for infection. Methods A reporter HSV-2 virus, which expresses beta-galactosidase, was used to quantify entry into RPE cells and viral replication was ascertained using a plaque assay. Flow cytometry and immunocytochemistry were used to determine cellular expression of entry receptors. Localization of these receptors to either the apical or basal surface of RPE cells was determined using immunocytochemistry. The necessity of these receptors, both individually and in combination, for viral entry was established using both receptor-specific antibodies and siRNAs. Results RPE are highly susceptible to HSV-2 entry and replication. Several assays demonstrated the expression of the entry receptors nectin-1, HVEM, and PILR-alpha and their localization primarily to the apical surface of RPE cells. Receptor-specific antibodies and siRNA knockdown of receptors significantly reduced viral entry and implicated nectin-1 as an important receptor with HVEM and PILR-alpha potentially also contributing to entry. Conclusions HSV-2 is capable of developing a productive infection in RPE cells by utilizing nectin-1 as an important entry receptor. To lesser degrees, HVEM and PILR-alpha may also contribute to HSV-2 entry into RPE cells.

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Expression of Nectin-1 in Normal and Herpes Simplex Virus Type 1-Infected Murine Brain

Cited by 19 publications

References 46 publications

The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

Heparanase is a host enzyme required for herpes simplex virus-1 release from cells

Role of Nectin-1, HVEM, and PILR-α in HSV-2 Entry into Human Retinal Pigment Epithelial Cells

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