Expression of Herpes Virus Entry Mediator (HVEM) in the Cornea and Trigeminal Ganglia of Normal and HSV-1 Infected Mice

Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that enters cells by the receptor-mediated fusion of the viral envelope with a host cell membrane. The envelope glycoprotein gD of HSV must bind to one of its receptors for entry to take place. Recent studies using knockout (KO) mice demonstrated that the gD receptors herpesvirus entry mediator (HVEM) and nectin-1 are the primary entry receptors for HSV-2 in the mouse vagina and brain. Nectin-1 was most crucial for the neuronal spread of HSV-2, particularly in the brain. HVEM was dispensable for infection in these models, but when both HVEM and nectin-1 were absent, infection was completely prevented. We sought to determine the receptor requirements of HSV-1 in an ocular model of infection using knockout mice. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double-KO mice were infected via corneal scarification and monitored for clinical signs of infection and viral replication in various tissues. We report that either HVEM or nectin-1 must be present for HSV-1 infection of the cornea. Additionally, we observed that the infection was attenuated in both HVEM KO and nectin-1 KO mice. This is in contrast to what was reported for studies of HSV-2 in vagina and brain and suggests that receptor requirements for HSV vary depending on the route of inoculation and/or serotype.Herpes simplex virus 1 (HSV-1), an alphaherpesvirus, is the leading cause of infectious blindness in developed countries (12). Infection begins in peripheral epithelial tissues, including the oral mucosal, skin, or corneal epithelium. After replicating in the epithelium, the virus infects adjacent neurons and travels via retrograde transport to sensory ganglia, including the trigeminal ganglia (TG) (1). In nerve cell bodies HSV is able to establish a life-long latent infection and reactivate at a later point or immediately undergo additional rounds of replication. During replication in neurons the virus can transit back down axons and reinfect the site of inoculation. HSV is also capable of spreading, in a zosteriform manner, to other peripheral tissues innervated by neurons from the infected ganglia. In rare cases in humans the virus can spread to the brain and cause encephalitis (7). HSV-1 is the predominant cause of ocular herpes infections and usually begins as conjunctivitis or epithelial keratitis. The reactivation of the virus can lead to subsequent damage to the cornea and stromal keratitis. This outcome depends on a variety of host and viral factors but often leads to blindness (2).The infectious cycle of HSV-1 begins when the virion envelope fuses with a host cell membrane either at the plasma membrane or in endocytic vesicles. Fusion is a complex process that requires multiple glycoproteins, including gD, gB, and the heterodimeric complex gH/gL (4). While the precise function of each glycoprotein remains unclear, it is well accepted that gD must bind to a gD receptor on the host cell for efficient entry. Several gD receptors have been identified, including herpesvirus entry ...

Section: Discussionmentioning

confidence: 62%

“…Earlier studies found that HVEM and nectin-1 are expressed in the epithelium of the murine cornea (9,28). Additionally, a more recent report stated that HVEM and nectin-1 are expressed on human corneal epithelial cells and that antibodies directed at these receptors reduced HSV-1 infection (20).…”

mentioning

confidence: 99%

Herpesvirus Entry Mediator and Nectin-1 Mediate Herpes Simplex Virus 1 Infection of the Murine Cornea

Karaba

Kopp

Longnecker

2011

“…However, it has been established that CD8 ϩ memory T cells infiltrate latently infected TGs in humans and mice, residing in close association with neurons (130,131). The close association of CD8 ϩ T cells, which typically express a variety of HVEM ligands (69), and neurons of the TG, which express HVEM (132), raises the question of direct effects of HVEM signaling on HSV latency. HVEM KO mice have lower rates of latency and reactivation than WT mice, although the HVEM KO strain also has lower titers in the eye initially, likely leading to decreased seeding of the TG (43, 133).…”

Section: Hvem Alters Host Immune Responses To Hsvmentioning

confidence: 99%

Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye

Edwards

Longnecker

2017

As its name suggests, the host receptor herpesvirus entry mediator (HVEM) facilitates herpes simplex virus (HSV) entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both tumor necrosis factor (TNF) and immunoglobulin (Ig) superfamilies with diverse, and often opposing, outcomes. While HVEM was first identified as a viral entry receptor for HSV, it is only recently that HVEM has emerged as an important host factor in immunopathogenesis of ocular HSV type 1 (HSV-1) infection. Surprisingly, HVEM exacerbates disease development in the eye independently of entry. HVEM signaling has been shown to play a variety of roles in modulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated pathogenesis in the eye. Here, we review the dual branches of HVEM function during HSV infection: entry and immunomodulation. HVEM is broadly expressed; intersects two important immunologic signaling networks; and impacts autoimmunity, infection, and inflammation. We hope that by understanding the complex range of effects mediated by this receptor, we can offer insights applicable to a wide variety of disease states.KEYWORDS HVEM, herpes simplex virus, herpes stromal keratitis H erpes simplex virus 1 (HSV-1) infects the majority of the world's population by adulthood and is responsible for the vast majority of ocular herpesvirus infections (1-3). In humans and mice, HSV-1 establishes lifelong latency in the trigeminal ganglia (TG) (4,5). Reactivations of HSV-1 in the TG can lead to anterograde movement of the virus along the ophthalmic branch of the trigeminal nerve, resulting in recurrent infection of virtually all the superficial tissues of the eye, including the cornea, conjunctiva, and eyelid (6-8). Ocular herpesvirus infections can lead to epithelial ulceration of the cornea, uveitis, and retinitis but most commonly cause herpes stromal keratitis, or HSK (9). HSK is characterized by chronic inflammation of the corneal stroma, leading to corneal thickening, opacification, scarring, and, potentially, blindness (10, 11). While reactivation accounts for the majority of human disease, most murine studies of HSK model primary infection as mice do not efficiently or reliably reactivate from latency (6).In the primary murine model of HSK, actively replicating HSV-1 in the cornea is detectable by plaque assay for up to 5 to 6 days postinfection (dpi) (9,12). Viral replication initiates HSK, as UV-inactivated or replication-deficient mutant HSV fail to induce HSK in BALB/c mice (13). However, HSK is an inflammatory disease, brought about by host infiltrates, particularly CD4 ϩ T cells and polymorphonuclear cells (PMN), that invade the murine cornea several days after replicating virus has been cleared and that persist chronically (14)(15)(16)(17)(18). A dizzying array of cytokines, chemokines, and immune cell types have been implicated in the pathogenesis of HSK, the temporal and...

“…This method is clearly distinct from the natural entry route of HSV, but these studies helped us to understand pathogenesis. Expression of nectin-1 and HVEM was observed in the epithelium of the murine cornea (15,16), and infection studies with HSV-1 in KO mice indicated attenuated disease in the absence of either HVEM or nectin-1 (17). In contrast, HSV-2 does not require HVEM to cause disease in corneal infections, suggesting that the HVEM requirement depends on the serotype (18).…”

mentioning

confidence: 99%

Entry Mechanisms of Herpes Simplex Virus 1 into Murine Epidermis: Involvement of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors

Petermann

Thier

Rahn

et al. 2015

Skin keratinocytes represent a primary entry site for herpes simplex virus 1 (HSV-1) in vivo. The cellular proteins nectin-1 and herpesvirus entry mediator (HVEM) act as efficient receptors for both serotypes of HSV and are sufficient for disease development mediated by HSV-2 in mice. How HSV-1 enters skin and whether both nectin-1 and HVEM are involved are not known. We addressed the impact of nectin-1 during entry of HSV-1 into murine epidermis and investigated the putative contribution of HVEM. Using ex vivo infection of murine epidermis, we showed that HSV-1 entered the basal keratinocytes of the epidermis very efficiently. In nectin-1-deficient epidermis, entry was strongly reduced. Almost no entry was observed, however, in nectin-1-deficient keratinocytes grown in culture. This observation correlated with the presence of HVEM on the keratinocyte surface in epidermis and with the lack of HVEM expression in nectin-1-deficient primary keratinocytes. Our results suggest that nectin-1 is the primary receptor in epidermis, while HVEM has a more limited role. For primary murine keratinocytes, on which nectin-1 acts as a single receptor, electron microscopy suggested that HSV-1 can enter both by direct fusion with the plasma membrane and via endocytic vesicles. Thus, we concluded that nectin-1 directs internalization into keratinocytes via alternative pathways. In summary, HSV-1 entry into epidermis was shown to strongly depend on the presence of nectin-1, but the restricted presence of HVEM can potentially replace nectin-1 as a receptor, illustrating the flexibility employed by HSV-1 to efficiently invade tissue in vivo. H erpes simplex viruses (HSV) are ubiquitous human pathogens which can cause a range of diseases, from mild, uncomplicated mucocutaneous lesions to life-threatening infections. HSV-1 is dominantly associated with orofacial infections and encephalitis, whereas HSV-2 more likely causes genital infections. To enter its human host, HSV must come into contact with mucosal surfaces, skin, or the cornea. During initial exposure on mucosa or skin, HSV targets epidermal keratinocytes and establishes a primary infection in the epithelium. Cellular entry of HSV relies on the interaction of several viral glycoproteins with various cell surface receptors (1, 2). The envelope glycoprotein D (gD) is essential for the entry process, and only after gD binding to a receptor is fusion with a cellular membrane induced (3). The major gD receptors mediating entry into mouse and human cells are herpesvirus entry mediator (HVEM) and nectin-1 (4-6). HVEM is a member of the tumor necrosis factor receptor superfamily which can activate either proinflammatory or inhibitory signaling pathways (7), while nectin-1 is an immunoglobulin-like cell adhesion molecule (8). A further gD receptor is 3-O-sulfated heparan sulfate, which may also play a role in HSV-1 entry into various cell types (9, 10).