Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1

Kopp, Sarah J.; Banisadr, Ghazal; Glajch, Kelly E.; Maurer, Ulrike E.; Grünewald, Kay; Miller, Richard J.; Osten, Pavel; Spear, Patricia G.

doi:10.1073/pnas.0908892106

Cited by 85 publications

(91 citation statements)

References 29 publications

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“…The very low infection efficiency might explain why double-KO mice were found to show no signs of infection with HSV (11)(12)(13). Since the 3-OS-HS generating 3-OST-3 enzyme (10) was detected in murine dermal fibroblasts, we suggest 3-OS-HS as a potential candidate to act as a rather inefficient receptor for HSV-1 on these cells.…”

Section: Discussionmentioning

confidence: 92%

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Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors for Herpes Simplex Virus 1 on Primary Murine Dermal Fibroblasts

Petermann

Rahn

Thier

et al. 2015

J Virol

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The cellular proteins nectin-1 and herpesvirus entry mediator (HVEM) can both mediate the entry of herpes simplex virus 1 (HSV-1). We have recently shown how these receptors contribute to infection of skin by investigating HSV-1 entry into murine epidermis. Ex vivo infection studies reveal nectin-1 as the primary receptor in epidermis, whereas HVEM has a more limited role. Although the epidermis represents the outermost layer of skin, the contribution of nectin-1 and HVEM in the underlying dermis is still open. Here, we analyzed the role of each receptor during HSV-1 entry in murine dermal fibroblasts that were deficient in expression of either nectin-1 or HVEM or both receptors. Because infection was not prevented by the absence of either nectin-1 or HVEM, we conclude that they can act as alternative receptors. Although HVEM was found to be highly expressed on fibroblasts, entry was delayed in nectin-1-deficient cells, suggesting that nectin-1 acts as the more efficient receptor. In the absence of both receptors, entry was strongly delayed leading to a much reduced viral spread and virus production. These results suggest an unidentified cellular component that acts as alternate but inefficient receptor for HSV-1 on dermal fibroblasts. Characterization of the cellular entry mechanism suggests that HSV-1 can enter dermal fibroblasts both by direct fusion with the plasma membrane and via endocytic vesicles and that this is not dependent on the presence or absence of nectin-1. Entry was also shown to require dynamin and cholesterol, suggesting comparable entry pathways in keratinocytes and dermal fibroblasts. IMPORTANCEHerpes simplex virus (HSV) is a human pathogen which infects its host via mucosal surfaces or abraded skin. To understand how HSV-1 overcomes the protective barrier of mucosa or skin and reaches its receptors in tissue, it is essential to know which receptors contribute to the entry into individual skin cells. Previously, we have explored the contribution of nectin-1 and herpesvirus entry mediator (HVEM) as receptors for HSV-1 entry into murine epidermis, where keratinocytes form the major cell type. Since the underlying dermis consists primarily of fibroblasts, we have now extended our study of HSV-1 entry to dermal fibroblasts isolated from nectin-1-or HVEM-deficient mice or from mice deficient in both receptors. Our results demonstrate a role for both nectin-1 and HVEM as receptors and suggest a further receptor which appears much less efficient.T o initiate infection, herpes simplex virus 1 (HSV-1) enters its human host via mucosal surfaces or abraded skin. HSV-1 entry into individual cells involves the interaction of several viral glycoproteins with various cell surface receptors (1, 2). The first step during entry is the attachment of virions to glycosaminoglycans, which facilitates the interaction with cellular receptors, leading to the fusion of the viral envelope with a cellular membrane. Fusion can either occur with the plasma membrane or with vesicle membranes after virions are int...

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Section: Discussionmentioning

confidence: 92%

“…Since the absence of both nectin-1 and HVEM prevents HSV pathogenesis in the mouse model, nectin-1 and HVEM are reported to be the dominant functional gD receptors in the murine host (11)(12)(13). Using nectin-1-or HVEM-deficient mice, we recently investigated HSV-1 entry into murine epidermis.…”

mentioning

confidence: 99%

Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors for Herpes Simplex Virus 1 on Primary Murine Dermal Fibroblasts

Petermann

Rahn

Thier

et al. 2015

J Virol

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“…It has also been studied in experimental animal diseases induced by hypoxic injury (13) or neurovirulent viruses, such as picornaviruses (14), measles virus (15), sindbis virus (16), HSV (17), and Borna disease virus (BDV) (18), or in injuries induced by a chemical agent (19). Depending on the causative agents and methods adopted to induce hippocampal injury, the injured subregions in the hippocampus vary; however, the reason for this selective vulnerability remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Mutant Murine Hepatitis Virus-Induced Apoptosis in the Hippocampus

2014

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SUMMARY:The mutant virus Mu-3 was isolated from the soluble receptor-resistant mutant 7 virus (srr7), which is a neuropathogenic strain of the mouse hepatitis virus JHMV, and cloned as a soluble receptor-resistant mutant from the highly neuropathogenic JHMV strain cl-2 virus (cl-2). In order to identify specific characteristcs of Mu-3, the pathology of Mu-3-infected mice was compared with that of srr7-and cl-2-infected mice. The neuropathology after Mu-3 infection exhibited a mixed pattern comparable to that induced by srr7 and cl-2 infections. In addition, Mu-3 infection caused marked apoptotic lesions in the hippocampal region, particularly in the CA2 and CA3 subregions, in the brains of all infected mice. In contrast, in cl-2 infection, 10-20z of the infected mice exhibited apoptosis in the hippocampus, which was primarily observed in the CA1 subregion. Apoptosis also occurred in the pyramidal neurons and CD11b-bearing cells. The apoptotic cells, indicated by caspase 3-activation, were a mixed population of infected and a higher number of uninfected cells. These data indicated that apoptosis observed in Mu-3 infection could be induced by the indirect effects of infection in addition to direct effects of the infected cells occurring in a cell-autonomous manner.

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“…Double-KO mice lacking both HVEM and nectin-1 were resistant to infection. Adult nectin-1 KO mice were resistant to encephalitis after direct intracerebral inoculation with HSV-2 (11). Interestingly, compared to that in WT mice, disease was attenuated in both HVEM KO and nectin-1 KO mice after corneal infection with HSV-1 (12).…”

mentioning

confidence: 96%

Pathogenesis of Neonatal Herpes Simplex 2 Disease in a Mouse Model Is Dependent on Entry Receptor Expression and Route of Inoculation

Kopp

Karaba

Cohen

et al. 2013

J Virol

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cHerpes simplex virus (HSV) pathogenesis in mice differs based on availability of the principal entry receptors herpesvirus entry mediator (HVEM) and nectin-1 in a manner dependent upon route of inoculation. After intravaginal or intracranial inoculation of adult mice, nectin-1 is a major mediator of neurologic disease, while the absence of either receptor attenuates disease after ocular infection. We tested the importance of receptor availability and route of infection on disease in mouse models of neonatal HSV. We infected 7-day-old mice lacking neither or one principal HSV receptor or both principal HSV receptors with HSV-2 via a peripheral route (intranasal), via a systemic route (intraperitoneal), or by inoculation directly into the central nervous system (intracranial). Mortality, neurologic disease, and visceral dissemination of virus were significantly attenuated in nectin-1 knockout mice compared with HVEM knockout or wild-type mice after intranasal inoculation. Mice lacking both entry receptors (double-knockout mice) showed no evidence of disease after inoculation by any route. Nectin-1 knockout mice had delayed mortality after intraperitoneal inoculation relative to wild-type and HVEM knockout mice, but virus was able to spread to the brain and viscera in all genotypes except double-knockout mice. Unlike in adult mice, HVEM was sufficient to mediate disease in neonatal mice after direct intracranial inoculation, and the absence of HVEM delayed time to mortality relative to that of wild-type mice. Additionally, in wild-type neonatal mice inoculated intracranially, HSV antigen did not primarily colocalize with NeuNpositive neurons. Our results suggest that differences in receptor expression between adults and newborns may partially explain differences in susceptibility to HSV-2. H erpes simplex virus (HSV) causes neonatal infection in about 1 in 3,200 live births in the United States (1). More than half of infants with neonatal HSV disease have disseminated disease or encephalitis (2), which, despite effective antiviral treatment, results in the deaths of more than 25% of those with disseminated disease and in neurologic morbidity in more than two-thirds of survivors of encephalitis (3). Relative to other populations infected with HSV, newborns have the highest rates of dissemination and central nervous system (CNS) disease (4). Although differences in immune responses from those of adults have been implicated, precise reasons for the increased severity of disease in infants remain unknown (5).Infection of susceptible human and mouse cells by HSV requires binding of the viral glycoprotein gD with one of its cell surface receptors (6, 7). HSV gD binds to three general classes of surface receptors, including herpesvirus entry mediator (HVEM), nectin-1 and Ϫ2, and specific sites in heparan sulfate (7). Of these, HVEM and nectin-1 appear to mediate viral entry most efficiently in both humans and mice (8, 9). The mouse receptors are orthologous to the human receptors, and HSV disease in mice resembles that i...

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Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1

Cited by 85 publications

References 29 publications

Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors for Herpes Simplex Virus 1 on Primary Murine Dermal Fibroblasts

Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors for Herpes Simplex Virus 1 on Primary Murine Dermal Fibroblasts

Mutant Murine Hepatitis Virus-Induced Apoptosis in the Hippocampus

Pathogenesis of Neonatal Herpes Simplex 2 Disease in a Mouse Model Is Dependent on Entry Receptor Expression and Route of Inoculation

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