Granulocytes in Ocular HSV-1 Infection: Opposing Roles of Mast Cells and Neutrophils

Royer, Derek J.; Zheng, Min; Conrady, Christopher D.; Carr, Daniel J.J.

doi:10.1167/iovs.15-16900

Cited by 48 publications

(62 citation statements)

References 70 publications

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“…High-titer challenges were conducted with 50,000-PFU inocula to determine the extent of vaccine-mediated protection. The McKrae strain was propagated and maintained at high titer as described previously (37). Mice were euthanized by cardiac perfusion with 10 to 15 ml of phosphatebuffered saline (PBS) for tissue collection and subsequent analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Edema and mechanosensation in healthy and HSV-1-infected corneas of vaccinated and naive mice were measured using a Corneo-Gage Plus digital pachymeter (Sonogage) and a handheld Cochet-Bonnet esthesiometer (Luneau Technology), respectively, as previously described (37,40). Labeling, imaging, and analysis of vasculature in cornea flat mounts were performed using an Olympus FV500 confocal microscope and MetaMorph Imaging Suite (Molecular Devices) as described previously (41).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, MLN pairs were macerated into single-cell suspensions in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1ϫ antibiotic/antimycotic, and 10 g/ml gentamicin (Gibco), i.e., complete medium. Corneas were digested in 2.0 mg/ml type 1 collagenase (Sigma) as described previously (37). Cell suspensions were filtered through 40-m-pore-size mesh, immunolabeled with eBioscience or AbD Serotec antibodies, washed, and fixed as previously described (37).…”

Section: Methodsmentioning

confidence: 99%

“…Corneas were digested in 2.0 mg/ml type 1 collagenase (Sigma) as described previously (37). Cell suspensions were filtered through 40-m-pore-size mesh, immunolabeled with eBioscience or AbD Serotec antibodies, washed, and fixed as previously described (37). Spleens were harvested and processed as described previously (37).…”

Section: Methodsmentioning

confidence: 99%

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A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

Royer

Gurung

Jinkins

et al. 2016

J Virol

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Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0⌬NLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0⌬NLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. Moreover, 0⌬NLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechanosensory function. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0⌬NLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency. IMPORTANCEHSV-1 manifests in a variety of clinical presentations ranging from a rather benign "cold sore" to more severe forms of infection, including necrotizing stromal keratitis and herpes simplex encephalitis. The present study was undertaken to evaluate a novel vaccine to ocular HSV-1 infection not only for resistance to viral replication and spread but also for maintenance of the visual axis. The results underscore the necessity to reconsider strategies that utilize attenuated live virus as opposed to subunit vaccines against ocular HSV-1 infection. Herpes simplex virus 1 (HSV-1) is a highly successful human pathogen that results in approximately 40,000 new cases of severe visual impairment each year (1). In such cases, the immune response to the pathogen inadvertently mediates corneal pathology. Moreover, the morbidity associated with ocular infection results from episodic viral recrudescence (2, 3). This etiology is dependent upon reactivation of HSV-1 from latently infected neurons within the trigeminal ganglion (TG), which innervates the cornea and orofacial mucosae. Although gamma interferon (IFN-␥) and other cytokines secreted by T cells and other cornearesident cells facilitate viral clearance in the cornea, these soluble factors also recruit neutrophils and activate macrophages replete with proteases that instigate extracellular matrix remodeling and scar formation, thereby compromising visual acuity (4-10). Furthermore, protracted inflammatory responses sustained beyond clearance of the virus contribute to corneal neovascularization (1, 11). Consequently, developing HSV vaccines that elicit robust protection against infection without enhancing the risk for corneal immunopathology is an important clinical matter as no sanctioned HSV vaccine clinical trials to dat...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

Royer

Gurung

Jinkins

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Samples were analyzed using a MacsQuant flow cytometer and MacsQuantify software version 2.6 (Miltenyi Biotec, Bergish Gladbach, Germany), as previously described. 29 Briefly, the phenotype of myeloid populations was based on a gating strategy that selects cells in the scatter range that are CD45 Protein Extraction, Suspension Array, and Western Blot Corneas were harvested and homogenized in T-PER tissue protein extraction reagent (Thermo Scientific, Pittsburgh, PA; 78510) supplemented with 1Â protease inhibitor cocktail (EMD Millipore; 539131) using a tissue miser. The supernatants from tissue homogenates were assayed for protein content using a BCA protein method (Thermo Scientific; 23225).…”

Section: Flow Cytometrymentioning

confidence: 99%

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Chucair-Elliott

Jinkins

Carr

et al. 2016

The American Journal of Pathology

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Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV-1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1einduced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression.

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The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

Peñaloza

Álvarez

Muñoz‐Durango

et al. 2018

Journal of Leukocyte Biology

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An effective pathogen has the ability to evade the immune response. The strategies used to achieve this may be based on the direct action of virulence factors or on the induction of host factors. Myeloid‐derived suppressor cells (MDSCs) are immune cells with an incredible ability to suppress the inflammatory response, which makes them excellent targets to be exploited by pathogenic bacteria, viruses, or parasites. In this review, we describe the origin and suppressive mechanisms of MDSCs, as well as their role in chronic bacterial, viral, and parasitic infections, where their expansion seems to be essential in the chronicity of the disease. We also analyze the disadvantages of current MDSC depletion strategies and the different in vitro generation methods, which can be useful tools for the deeper study of these cells in the context of microbial infections.

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Granulocytes in Ocular HSV-1 Infection: Opposing Roles of Mast Cells and Neutrophils

Cited by 48 publications

References 70 publications

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

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