Corneal lymphangiogenesis in herpetic stromal keratitis

Park, Paul J.; Chang, Michael; Garg, Nitin; Zhu, Jimmy; Chang, Jin Hong; Shukla, Deepak

doi:10.1016/j.survophthal.2014.06.001

Cited by 31 publications

(23 citation statements)

References 151 publications

(213 reference statements)

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“…These include corneal scarring, neovascularization, and sensation loss, all of which are recapitulated in the animal model of ocular infection (11,45,46,51,70). Phylogenetic differences among virulence determinants in different HSV-1 strains are associated with various degrees of corneal neovascularization (71).…”

Section: Discussionmentioning

confidence: 99%

“…6E) at day 30 p.i. We interpret this final evidence to indicate that the homologous recombination utilized to modify the ICP0 coding sequence in the HSV-1 0ΔNLS strain did not affect the ability of the strain to express LAT or the fidelity of detection by PCR, despite the partially overlapping coding sequences of the LAT and ICP0 genes on cDNA strands of the HSV-1 genome (51,53,54).…”

mentioning

confidence: 92%

“…Corneal neovascularization is another hallmark of herpetic eye disease for which the host immune response is thought to play an important role (49)(50)(51)(52). Accordingly, corneas were harvested from mice ocularly infected with HSV-1 0ΔNLS or KOS-GFP at day 30 p.i.…”

mentioning

confidence: 99%

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Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Royer

Carr

Chucair-Elliott

et al. 2017

J Virol

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Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS) on the ICP0 gene (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-␤) in vitro and functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response and in vivo pathogenesis of HSV-1 0ΔNLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-␣/␤) signaling on virulence and immunogenicity of HSV-1 0ΔNLS and uncover a probable sex bias in the induction of IFN-␣/␤ in the cornea during HSV-1 infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-␣/␤ receptor. These studies support the translational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0ΔNLS does not induce significant tissue pathology.IMPORTANCE HSV-1 is a common human pathogen associated with a variety of clinical presentations ranging in severity from periodic "cold sores" to lethal encephalitis. Despite the consistent failures of HSV subunit vaccines in clinical trials spanning the past 28 years, opposition to live-attenuated HSV vaccines predicated on unfounded safety concerns currently limits their widespread acceptance. Here, we demonstrate that a live-attenuated HSV-1 vaccine has great translational potential.KEYWORDS HSV-1, T cells, antibody, cornea, mouse, neovascularization S trategies for vaccine development have transitioned largely from empirical to so-called "next-generation" or rational approaches during the past 2 decades, a shift largely driven by technological advances and a better understanding of how innate immunity influences the generation of adaptive protection (1, 2). Despite these breakthroughs, the average person still acquires multiple herpesvirus infections during childhood (3). A licensed vaccine, however, exists only for varicella-zoster virus (VZV) (4). The live-attenuated Oka vaccine for VZV is generally well tolerated and has significantly reduced the incidence of VZV infection, morbidity, and mortality in the United States (5, 6). Furthermore, epidemiologic studies indicate that acquisition of herpes simplex virus 1 (HSV-1) has shifted toward early to late adolescence in recent decades within the United States, potentially creating an opportunity to introduce an effective prophylactic HSV-1 vaccine into the childhood vaccine regimen (7). HSV vaccines have been tested in multiple clinical trials, but these studies have focused on protein subunit vaccines

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

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Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Royer

Carr

Chucair-Elliott

et al. 2017

J Virol

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“…Although most of the studies on immunoprivilege have focused on the anterior chamber (anterior chamber-associated immune deviation [ACAID]) or the retina (17)(18)(19), the cornea also has some features that suppress inflammation. Most notably, these are reduced constitutive major histocompatibility complex expression and a lack of vascularization and lymphatic vessels in the cornea (20,21). Despite these protective mechanisms, inflammatory responses do occur.…”

Section: Discussionmentioning

confidence: 99%

“…tory cytokines and chemokines that result in the recruitment of neutrophils and then various types of T cells into the cornea (21)(22)(23)(24). For some infections, like HSV infections, blood vessels and lymphatics infiltrate into the cornea, amplifying the response.…”

Section: Fig 9 Flow Cytometry Analysis Of T-cell Subsets In Infected mentioning

confidence: 99%

Both CD8⁺and CD4⁺T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice

Larsen

Clausius

Kolb

et al. 2016

J Virol

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Vaccinia virus (VACV) keratitis is a serious complication following smallpox vaccination and can lead to blindness. The pathological mechanisms involved in ocular VACV infection are poorly understood. Previous studies have used rabbits, but the lack of immune reagents and transgenic or knockout animals makes them less suitable for mechanistic studies. We report that infection of C57BL/6 mice with 1 ؋ 10 7 PFU of vaccinia virus strain WR results in blepharitis, corneal neovascularization, and stromal keratitis. The DryVax strain of VACV was completely attenuated. Infection required corneal scarification and replication-competent virus, and the severity of ocular disease was similar in 4-to 6-week-old and 1-year-old mice. Viral titers peaked at approximately 1 ؋ 10 6 PFU on day 5 postinfection, and virus had not cleared by day 13 postinfection. Neutrophils were found in the peripheral cornea on day 1 after infection and then declined, followed by infiltration of both CD4؉ and CD8 ؉ T cells, which remained peripheral throughout the infection. Blood vessel growth extended 2 to 5 mm into the cornea from the limbus. Infection of CD4 ؊/؊ , CD8 ؊/؊ , or antibody-depleted mice resulted in similar disease severity and corneal clouding, indicating that both T-cell subsets were involved in the immunopathological response. Depletion of both CD4؉ and CD8 ؉ T cells resulted in significantly more severe disease and failure to clear the virus. On the basis of our results, the pathology of VACV keratitis is significantly different from that of herpes simplex virus keratitis. Further studies are likely to reveal novel information regarding virulence and immune responses to viral ocular infection. IMPORTANCEPotentially blinding eye infections can occur after vaccination for smallpox. Very little is known about the pathological mechanisms that are involved, and the information that is available was generated using rabbit models. The lack of immunological reagents for rabbits makes such studies difficult. We characterized a mouse model of vaccinia virus ocular disease using C57BL/6 mice and strain WR and show that both CD4؉ and CD8 ؉ T-cell subsets play a role in the blinding eye disease and in controlling virus replication. On the basis of these results, vaccinia virus keratitis is significantly different from herpes simplex virus keratitis, and further studies using this model should generate novel insights into immunopathological responses to viral ocular infection. In 1977, the World Health Organization reported the last known case of naturally acquired smallpox virus infection (1). The eradication of smallpox was accomplished by rigorous vaccination using vaccinia virus (VACV) and a contact tracing program. Shortly thereafter, the United States stopped vaccination of the general population. In response to increased terrorism incidents, including bioterror events, the U.S. government expanded the list of those who should be vaccinated to include first responders and stockpiled smallpox vaccine and vaccinia virus immune gl...

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Ocular Immunopathology

Ramos¹,

Teixeira²,

Brandt³

et al. 2017

Immunopathology in Toxicology and Drug Development

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Corneal lymphangiogenesis in herpetic stromal keratitis

Cited by 31 publications

References 151 publications

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Both CD8⁺and CD4⁺T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice

Ocular Immunopathology

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Corneal lymphangiogenesis in herpetic stromal keratitis

Cited by 31 publications

References 151 publications

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Both CD8+and CD4+T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice

Ocular Immunopathology

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Both CD8⁺and CD4⁺T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice