scholarly journals Characterization of Sex Differences in Ocular Herpes Simplex Virus 1 Infection and Herpes Stromal Keratitis Pathogenesis of Wild-Type and Herpesvirus Entry Mediator Knockout Mice

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Rachel E. Riccio ◽  
Seo J. Park ◽  
Richard Longnecker ◽  
Sarah J. Kopp
Keyword(s):  
Sex Differences ◽  
Immune Cell ◽  
Herpes Simplex Virus 1 ◽  
Male And Female ◽  
Biological Variable ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Herpes Stromal Keratitis ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACTSex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050–1059, 2012,https://doi.org/10.1002/bies.201200099). Herpes simplex virus 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune-privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, et al., Prog Retin Eye Res 32:88–101, 2013,https://doi.org/10.1016/j.preteyeres.2012.08.002). Our research focuses on the role of herpesvirus entry mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM knockout [KO] mice) exhibit lower levels of immune cell infiltrates and less severe ocular disease in the cornea than wild-type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested whether sex acts as a biological variable in the immune response to HSV-1 infection and herpes stromal keratitis (HSK) pathogenesis. Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers were determined, and immune cell infiltrates were collected and analyzed. Our results indicated no significant differences in viral titers in tear film or affected tissues, in immune cell infiltration, or in clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model and that male and female mice of the C57BL/6 background can be used similarly in studies of ocular HSV-1 pathogenesis.IMPORTANCESex hormones have come to be considered an important factor for the development of certain diseases only recently and as such should continue to be considered a biological variable. Ocular HSV-1, and the resulting HSK, is the leading cause of infectious blindness worldwide. We compared levels of ocular HSV-1 infection and pathogenesis in the two sexes and found no significance differences between male and female WT mice or HVEM KO mice.

scholarly journals Characterization of Sex Differences in Ocular HSV-1 Infection and Herpes Stromal Keratitis Pathogenesis of Wild Type and Herpesvirus Entry Mediator Knockout Mice

2019 ◽  
Author(s):  
Rachel E Riccio ◽  
Seo J Park ◽  
Richard M Longnecker ◽  
Sarah J Kopp
Keyword(s):  
Sex Differences ◽  
Immune Cell ◽  
Wild Type ◽  
Male And Female ◽  
Biological Variable ◽  
Stromal Keratitis ◽  
Herpes Stromal Keratitis ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACTSex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050-9, 2012). Herpes simplex virus type 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, J. E. Knickelbein, and E. Vilain, Prog Retin Eye Res 32:88-101, 2013). Our research focuses on the role of Herpes Viral Entry Mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM KO) exhibit lower immune cell infiltrates and less severe ocular disease in the cornea compared to wild type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested sex as a biological variable in the immune response to HSV-1 infection and Herpes Stromal Keratitis pathogenesis (HSK). Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers and immune cell infiltrates were collected and analyzed. Our results indicate no significant difference in viral titers in tear film or affected tissues; immune cell infiltration; or clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model, and that male and female mice can similarly be used in studies of ocular HSV-1 pathogenesis.IMPORTANCESex hormones have only recently been considered as an important factor for the development of certain diseases and as such should continue to be considered as a biological variable. Ocular Herpesvirus Type 1 (HSV-1), and the resulting Herpes Stromal Keratitis, is the leading cause of infectious blindness worldwide. We compared ocular HSV-1 infection and pathogenesis between sexes and found no significance difference between male and female wild type mice or herpesvirus entry mediator knockout mice. Therefore, male and female mice can be used interchangeably in studying ocular HSV-1 pathogenesis.

scholarly journals Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Nisha R. Dhanushkodi ◽  
Ruchi Srivastava ◽  
Pierre-Gregoire A. Coulon ◽  
Swayam Prakash ◽  
Soumyabrata Roy ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Herpes Simplex Virus 1 ◽  
Cytokines And Chemokines ◽  
Latently Infected ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.

scholarly journals Herpes Simplex Virus 1 Latency and the Kinetics of Reactivation Are Regulated by a Complex Network of Interactions between the Herpesvirus Entry Mediator, Its Ligands (gD, BTLA, LIGHT, and CD160), and the Latency-Associated Transcript

2018 ◽  
Vol 92 (24) ◽  
Author(s):  
Shaohui Wang ◽  
Alexander V. Ljubimov ◽  
Ling Jin ◽  
Klaus Pfeffer ◽  
Mitchell Kronenberg ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Trigeminal Ganglia ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Latently Infected ◽  
Simplex Virus ◽  
Kinetics Of ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACTRecently, we reported that the herpesvirus entry mediator (HVEM; also called TNFRSF14 or CD270) is upregulated by the latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1) and that the absence of HVEM affects latency reactivation but not primary infection in ocularly infected mice. gD has been shown to bind to HVEM. LIGHT (TNFSF14), CD160, and BTLA (B- and T-lymphocyte attenuator) also interact with HVEM and can interfere with HSV gD binding. It was not known if LIGHT, CD160, or BTLA affected the level of latency reactivation in the trigeminal ganglia (TG) of latently infected mice. To address this issue, we ocularly infected LIGHT−/−, CD160−/−, and BTLA−/−mice with LAT(+) and LAT(−) viruses, using similarly infected wild-type (WT) and HVEM−/−mice as controls. The amount of latency, as determined by the levels of gB DNA in the TG of the LIGHT−/−, CD160−/−, and BTLA−/−mice infected with either LAT(+) or LAT(−) viruses, was lower than that in WT mice infected with LAT(+) virus and was similar in WT mice infected with LAT(−) virus. The levels of LAT RNA in HVEM−/−, LIGHT−/−, CD160−/−, and BTLA−/−mice infected with LAT(+) virus were similar and were lower than the levels of LAT RNA in WT mice. However, LIGHT−/−, CD160−/−, and BTLA−/−mice, independent of the presence of LAT, had levels of reactivation similar to those of WT mice infected with LAT(+) virus. Faster reactivation correlated with the upregulation of HVEM transcript. The LIGHT−/−, CD160−/−, and BTLA−/−mice had higher levels of HVEM expression, and this, along with the absence of BTLA, LIGHT, or CD160, may contribute to faster reactivation, while the absence of each molecule, independent of LAT, may have contributed to lower latency. This study suggests that, in the absence of competition with gD for binding to HVEM, LAT RNA is important for WT levels of latency but not for WT levels of reactivation.IMPORTANCEThe effects of BTLA, LIGHT, and CD160 on latency reactivation are not known. We show here that in BTLA, LIGHT, or CD160 null mice, latency is reduced; however, HVEM expression is upregulated compared to that of WT mice, and this upregulation is associated with higher reactivation that is independent of LAT but dependent on gD expression. Thus, one of the mechanisms by which BTLA, LIGHT, and CD160 null mice enhance reactivation appears to be the increased expression of HVEM in the presence of gD. Thus, our results suggest that blockade of HVEM-LIGHT-BTLA-CD160 contributes to reduced HSV-1 latency and reactivation.

scholarly journals Herpesvirus Entry Mediator on Radiation-Resistant Cell Lineages Promotes Ocular Herpes Simplex Virus 1 Pathogenesis in an Entry-Independent Manner

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Rebecca G. Edwards ◽  
Sarah J. Kopp ◽  
Andrew H. Karaba ◽  
Douglas R. Wilcox ◽  
Richard Longnecker
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Entry ◽  
Resistant Cell ◽  
Herpes Simplex Virus 1 ◽  
Ocular Herpes ◽  
Radiation Resistant ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTOcular 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.IMPORTANCEImmune privilege is maintained in the eye in order to protect specialized ocular tissues, such as the translucent cornea, from vision-reducing damage. Ocular herpes simplex virus 1 (HSV-1) infection can disrupt this immune privilege, provoking a host response that ultimately brings about the majority of the damage seen with the immunoinflammatory syndrome herpes stromal keratitis (HSK). Our previous work has shown that HVEM, a host TNF receptor superfamily member that also serves as a viral entry receptor, is a critical component contributing to ocular HSV-1 pathogenesis, although its precise role in this process remains unclear. We hypothesized that HVEM promotes an inflammatory microenvironment in the eye through immunomodulatory actions, enhancing disease after ocular inoculation of HSV-1. Investigating the mechanisms responsible for orchestrating this aberrant immune response shed light on the initiation and maintenance of HSK, one of the leading causes of infectious blindness in the developed world.

scholarly journals OPTN limits herpes stromal keratitis severity and demyelination through negative regulation of IL-17 and hyperinflammatory T-cell response

2021 ◽  
Author(s):  
Joshua M Ames ◽  
Tejabhiram Yadavalli ◽  
Chandrashekhar Patil ◽  
James Hopkins ◽  
Ilina Bhattacharya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Clinical Manifestations ◽  
T Cell Response ◽  
Host Restriction ◽  
Viral Spread ◽  
Stromal Keratitis ◽  
Herpes Stromal Keratitis ◽  
Hsv 1

Herpes stromal keratitis (HSK) is a result of the inflammatory sequelae following primary and recurrent Herpes simplex virus type-1 (HSV-1) infections. This pathology is known to be mediated by immunopathogenic T cell responses against viral antigens, however most individuals infected with HSV-1 never exhibit signs of this immunopathology. Recent studies have identified the host restriction factor, optineurin (OPTN), as an inhibitor of viral spread in the central nervous system, protecting hosts from viral encephalopathy. In an HSV-1 corneal infection mouse model on OPTN knockout mice, we assess the contribution of OPTN to ameliorating the clinical manifestations of HSK. We identify that OPTN protects the host from loss of ocular and whisker sensitivity and opacification of the cornea. scRNA-seq of the trigeminal ganglion (TG) reveals that transcription changes to the peripheral neurons and immune cell populations drive the expression of Il-17A in CD4 and CD8 T cells, as well as increased infiltration of T cells into the TG. This leads to demyelination and the observed HSK pathology.

scholarly journals Advancing Our Understanding of Corneal Herpes Simplex Virus-1 Immune Evasion Mechanisms and Future Therapeutics

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1856
Author(s):  
Emily Greenan ◽  
Sophie Gallagher ◽  
Rana Khalil ◽  
Conor C. Murphy ◽  
Joan Ní Gabhann-Dromgoole
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Treatment Options ◽  
Topical Steroids ◽  
Herpes Simplex Virus 1 ◽  
Corneal Scarring ◽  
Disease Reactivation ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Hsv 1

Herpes stromal keratitis (HSK) is a disease that commonly affects the cornea and external eye and is caused by Herpes Simplex Virus type 1 (HSV-1). This virus infects approximately 66% of people worldwide; however, only a small portion of these people will develop symptoms in their lifetime. There is no cure or vaccine available for HSV-1; however, there are treatments available that aim to control the inflammation caused by the virus and prevent its recurrence. While these treatments are beneficial to those suffering with HSK, there is a need for more effective treatments to minimise the need for topical steroids, which can have harmful effects, and to prevent bouts of disease reactivation, which can lead to progressive corneal scarring and visual impairment. This review details the current understanding of HSV-1 infection and discusses potential novel treatment options including microRNAs, TLRs, mAbs, and aptamers.

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

2014 ◽  
Vol 89 (1) ◽  
pp. 262-274 ◽  
Author(s):  
Philipp Petermann ◽  
Katharina Thier ◽  
Elena Rahn ◽  
Frazer J. Rixon ◽  
Wilhelm Bloch ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Ex Vivo ◽  
Target Tissue ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
The Impact ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACTSkin 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. Usingex vivoinfection 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 tissuein vivo.IMPORTANCEHerpes simplex virus (HSV) can cause a range of diseases in humans, from uncomplicated mucocutaneous lesions to life-threatening infections. The skin is one target tissue of HSV, and the question of how the virus overcomes the protective skin barrier and penetrates into the tissue to reach its receptors is still open. Previous studies analyzing entry into cells grownin vitrorevealed nectin-1 and HVEM as HSV receptors. To explore the contributions of nectin-1 and HVEM to entry into a natural target tissue, we established anex vivoinfection model. Using nectin-1- or HVEM-deficient mice, we demonstrated the distinct involvement of nectin-1 and HVEM for HSV-1 entry into epidermis and characterized the internalization pathways. Such advances in understanding the involvement of receptors in tissue are essential preconditions for unraveling HSV invasion of skin, which in turn will allow the development of antiviral reagents.

scholarly journals Invasion of Herpes Simplex Virus 1 into Murine Dermis: Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors during Aging

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Lisa Wirtz ◽  
Maureen Möckel ◽  
Dagmar Knebel-Mörsdorf
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dermal Fibroblasts ◽  
Target Tissue ◽  
Herpes Simplex Virus 1 ◽  
Infection Efficiency ◽  
Infected Cells ◽  
Simplex Virus ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACT Skin is a major target tissue of herpes simplex virus 1 (HSV-1), and we are only beginning to understand how individual receptors contribute to the initiation of infection in tissue. We recently demonstrated the impact of the receptors nectin-1 and herpesvirus entry mediator (HVEM) for entry of HSV-1 into murine epidermis. Here, we focus on viral invasion into the dermis, a further critical target tissue in vivo. In principle, murine dermal fibroblasts are highly susceptible to HSV-1, and we previously showed that nectin-1 and HVEM can act as alternative receptors. To characterize their contribution as receptors in dermal tissue, we established an ex vivo infection assay of murine dermis. Only after separation of the epidermis from the dermis, we observed single infected cells in the upper dermis from juvenile mice at 5 h postinfection with increasing numbers of infected cells at later times. While nectin-1-expressing cells were less frequently detected, we found HVEM expressed on most cells of juvenile dermis. The comparison of infection efficiency during aging revealed a strong delay in the onset of infection in the dermis from aged mice. This observation correlated with a decrease in nectin-1-expressing fibroblasts during aging while the number of HVEM-expressing cells remained stable. Accordingly, aged nectin-1-deficient dermis was less susceptible to HSV-1 than the dermis from control mice. Thus, we conclude that the reduced availability of nectin-1 in aged dermis is a key contributor to a decrease in infection efficiency during aging. IMPORTANCE HSV-1 is a prevalent human pathogen which invades skin and mucocutaneous linings. So far, the underlying mechanisms of how the virus invades tissue, reaches its receptors, and initiates infection are still unresolved. To unravel the mechanical prerequisites that limit or favor viral invasion into tissue, we need to understand the contribution of the receptors that are involved in viral internalization. Here, we investigated the invasion process into murine dermis with the focus on receptor availability and found that infection efficiency decreases in aging mice. Based on studies of the expression of the receptors nectin-1 and HVEM, we suggest that the decreasing number of nectin-1-expressing fibroblasts leads to a delayed onset of infection in the dermis from aged compared to juvenile mice. Our results imply that the level of infection efficiency in murine dermis is closely linked to the availability of the receptor nectin-1 and can change during aging.

scholarly journals Herpesvirus Entry Mediator Binding Partners Mediate Immunopathogenesis of Ocular Herpes Simplex Virus 1 Infection

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Seo J. Park ◽  
Rachel E. Riccio ◽  
Sarah J. Kopp ◽  
Igal Ifergan ◽  
Stephen D. Miller ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Response ◽  
Herpes Simplex Virus 1 ◽  
Binding Partners ◽  
Ocular Herpes ◽  
Simplex Virus ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACT Ocular herpes simplex virus 1 (HSV-1) infection leads to an immunopathogenic disease called herpes stromal keratitis (HSK), in which CD4+ T cell-driven inflammation contributes to irreversible damage to the cornea. Herpesvirus entry mediator (HVEM) is an immune modulator that activates stimulatory and inhibitory cosignals by interacting with its binding partners, LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160. We have previously shown that HVEM exacerbates HSK pathogenesis, but the involvement of its binding partners and its connection to the pathogenic T cell response have not been elucidated. In this study, we investigated the role of HVEM and its binding partners in mediating the T cell response using a murine model of ocular HSV-1 infection. By infecting mice lacking the binding partners, we demonstrated that multiple HVEM binding partners were required for HSK pathogenesis. Surprisingly, while LIGHT−/−, BTLA−/−, and CD160−/− mice did not show differences in disease compared to wild-type mice, BTLA−/− LIGHT−/− and CD160−/− LIGHT−/− double knockout mice showed attenuated disease characterized by decreased clinical symptoms, increased retention of corneal sensitivity, and decreased infiltrating leukocytes in the cornea. We determined that the attenuation of disease in HVEM−/−, BTLA−/− LIGHT−/−, and CD160−/− LIGHT−/− mice correlated with a decrease in gamma interferon (IFN-γ)-producing CD4+ T cells. Together, these results suggest that HVEM cosignaling through multiple binding partners induces a pathogenic Th1 response to promote HSK. This report provides new insight into the mechanism of HVEM in HSK pathogenesis and highlights the complexity of HVEM signaling in modulating the immune response following ocular HSV-1 infection. IMPORTANCE Herpes simplex virus 1 (HSV-1), a ubiquitous human pathogen, is capable of causing a progressive inflammatory ocular disease called herpes stromal keratitis (HSK). HSV-1 ocular infection leads to persistent inflammation in the cornea resulting in outcomes ranging from significant visual impairment to complete blindness. Our previous work showed that herpesvirus entry mediator (HVEM) promotes the symptoms of HSK independently of viral entry and that HVEM expression on CD45+ cells correlates with increased infiltration of leukocytes into the cornea during the chronic inflammatory phase of the disease. Here, we elucidated the role of HVEM in the pathogenic Th1 response following ocular HSV-1 infection and the contribution of HVEM binding partners in HSK pathogenesis. Investigating the molecular mechanisms of HVEM in promoting corneal inflammation following HSV-1 infection improves our understanding of potential therapeutic targets for HSK.

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