PurposeTo determine cellular and temporal expression patterns of herpes virus entry mediator (HVEM, Tnfrsf14) in the murine cornea during the course of herpes simplex virus 1 (HSV-1) infection, the impact of this expression on pathogenesis, and whether alterations in HVEM or downstream HVEM-mediated effects ameliorate corneal disease.MethodsCorneal HVEM levels were assessed in C57BL/6 mice after infection with HSV-1(17). Leukocytic infiltrates and corneal sensitivity loss were measured in the presence, global absence (HVEM knockout [KO] mice; Tnfrsf14−/−), or partial absence of HVEM (HVEM conditional KO). Effects of immune-modifying nanoparticles (IMPs) on viral replication, corneal sensitivity, and corneal infiltrates were measured.ResultsCorneal HVEM+ populations, particularly monocytes/macrophages during acute infection (3 days post infection [dpi]) and polymorphonuclear neutrophils (PMN) during the chronic inflammatory phase (14 dpi), increased after HSV-1 infection. Herpes virus entry mediator increased leukocytes in the cornea and corneal sensitivity loss. Ablation of HVEM from CD45+ cells, or intravenous IMP therapy, reduced infiltrates in the chronic phase and maintained corneal sensitivity.ConclusionsHerpes virus entry mediator was expressed on two key populations: corneal monocytes/macrophages and PMNs. Herpes virus entry mediator promoted the recruitment of myeloid cells to the cornea in the chronic phase. Herpes virus entry mediator–associated corneal sensitivity loss preceded leukocytic infiltration, suggesting it may play an active role in recruitment. We propose that HVEM on resident corneal macrophages increases nerve damage and immune cell invasion, and we showed that prevention of late-phase infiltration of PMN and CD4+ T cells by IMP therapy improved clinical symptoms and mortality and reduced corneal sensitivity loss caused by HSV-1.
Ocular herpes simplex virus 1 (HSV-1) infection leads to a potentially blinding immunoinflammatory syndrome, herpes stromal keratitis (HSK). Herpesvirus entry mediator (HVEM), a widely expressed tumor necrosis factor (TNF) receptor superfamily member with diverse roles in immune signaling, facilitates viral entry through interactions with viral glycoprotein D (gD) and is important for HSV-1 pathogenesis. We subjected mice to corneal infection with an HSV-1 mutant in which HVEM-mediated entry was specifically abolished and found that the HVEM-entry mutant produced clinical disease comparable to that produced by the control virus. HVEM-mediated induction of corneal cytokines, which correlated with an HVEM-dependent increase in levels of corneal immune cell infiltrates, was also gD independent. Given the complexity of HVEM immune signaling, we used hematopoietic chimeric mice to determine which HVEM-expressing cells mediate HSV-1 pathogenesis in the eye. Regardless of whether the donor was a wild-type (WT) or HVEM knockout (KO) strain, HVEM KO recipients were protected from ocular HSV-1, suggesting that HVEM on radiation-resistant cell types, likely resident cells of the cornea, confers wild-type-like susceptibility to disease. Together, these data indicate that HVEM contributes to ocular pathogenesis independently of entry and point to an immunomodulatory role for this protein specifically on radiation-resistant cells.
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...
The conserved chromatin remodeling and assembly factor CHD1 (chromodomains, helicase, DNA-binding domain) is present at active genes where it participates in histone turnover and recycling during transcription. In order to gain a more complete understanding of the mechanism of action of CHD1 during development, we created a novel genetic assay in Drosophila melanogaster to evaluate potential functional interactions between CHD1 and other chromatin factors. We found that overexpression of CHD1 results in defects in wing development and utilized this fully penetrant and reliable phenotype to conduct a small-scale RNAi-based candidate screen to identify genes that functionally interact with chd1 in vivo. Our results indicate that CHD1 may act in opposition to other remodeling factors, including INO80, and that the recruitment of CHD1 to active genes by RTF1 is conserved in flies.
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