Immunity causing blindness: five different paths to herpes stromal keratitis

doi:10.1016/S0167-5699(97)01114-6

Immunology Today

Volume 18, Issue 9, September 1997, Pages 443-449

Immunology Today

https://doi.org/10.1016/S0167-5699(97)01114-6 Get rights and content

Abstract

Herpes stromal keratitis (HSK) is a blinding infections disease that results from an array of immunopathogenic processes, including herpes simplex virus 1 (HSV-1)-specific T helper 1 (Th1) and Th2 cells, cytotoxic T cells and antibodies. As discussed here by Wayne Streilein and colleagues, strategies designed to prevent and treat this syndrome must be aware of the fact that the disease is multifactorial in its cause and pathogenesis.

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Herpes simplex virus type 1 (HSV-1) Keratitis (HSK) is a highly prevalent eye disease worldwide, characterized by lifelong recurrent episodes and a major risk of leading to blindness. Detecting HSV-1 promptly and accurately can initiate a timely and appropriate therapeutic regimen, minimizing tissue damage and preventing vision impairment. Currently, PCR is the most reliable method for identifying HSV-1, but its utilization for point-of-care (POC) HSV-1 detection is limited due to the need for sophisticated equipment, particularly in areas with limited resources. Here, we propose a new method for on-site HSV detection by using LAMP-Cas12 diagnostic technology and gold nanoparticles. This technique possesses comparable sensitivity to qPCR, and its detection results could be easily read and interpreted without the need for complex equipment. In detecting HSV in clinical tear specimens, this strategy achieved a 93.9 % consistency in positive detection and a 100 % consistency in negative detection compared to qPCR. Our strategy innovates the technique of current HSV-1 detections and is expected to play a crucial role in POC diagnosis of HSK in the future.
Controlling viral inflammatory lesions by inhibiting fatty acid metabolism
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Herpes simplex virus infection is a major cause of vision loss in humans. Eye damaging consequences are often driven by inflammatory cells as a result of an immune response to the virus. In the present report, we have compared the effect of inhibiting energy metabolism with etomoxir (Etox), which acts on the fatty acid oxidation pathway and 2-Deoxy-d-glucose (2DG), which acts on glycolysis for their inhibitory effects on herpetic ocular lesions. Both drugs showed similar protective effects when therapy was started on the day of infection, but some 2DG recipients succumbed to encephalitis. In contrast, all Etox recipients remained healthy. Both drugs were compared for effects on inflammatory reactions in the trigeminal ganglion (TG), where virus replicates and then establishes latency. Results indicate that 2DG significantly reduced CD8 and CD4 Th1 T cells in the TG, whereas Etox had minimal or no effect on such cells, perhaps explaining why encephalitis occurred only in 2DG recipients. Unlike treatment with 2DG, Etox therapy was largely ineffective when started at the time of lesion expression. Reasons for the differential effects were discussed as was the relevance of combining metabolic reprogramming approaches to combat viral inflammatory lesions.
Modulating glutamine metabolism to control viral immuno-inflammatory lesions
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Citation Excerpt :
Periodic recurrences can occur and these are particularly troublesome in some locations, such as the eye since they can result in blindness [2]. With chronic ocular lesions, the tissue damage that occurs is largely the consequence of immune reactivity to the infection [2,3] mediated mainly by neutrophils [4,5] and some types of macrophages [6,7]. However the inflammatory reaction is orchestrated by subsets of T cells, particularly CD4+ Th1 [8], CD4+ Th17 cells [9] and CD8+ T cells [10,11].
Infection of the cornea with HSV results in an immune-inflammatory reaction orchestrated by proinflammatory T cells that is a major cause of human vision impairment. The severity of lesions can be reduced if the representation of inflammatory T cells is changed to increase the presence of T cells with regulatory function. This report shows that inhibiting glutamine metabolism using 6-Diazo-5-oxo-l-norleucine (DON) administered via intraperitoneal (IP) starting 6 days after ocular infection and continued until day 15 significantly reduced the severity of herpetic stromal keratitis lesions. The therapy resulted in reduced neutrophils, macrophages as well proinflammatory CD4 Th1 and Th17 T cells in the cornea, but had no effect on levels of regulatory T cells. A similar change in the representation of inflammatory and regulatory T cells occurred in the trigeminal ganglion (TG) the site where HSV infection establishes latency. Glutamine metabolism was shown to be required for the in-vitro optimal induction of both Th1 and Th17 T cells but not for the induction of Treg that were increased when glutamine metabolism was inhibited. Inhibiting glutamine metabolism also changed the ability of latently infected TG cells from animals previously infected with HSV to reactivate and produce infectious virus.
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The trigeminal nerve gives rise to the corneal subbasal nerve system, which plays a crucial role in sensations of touch, pain, and temperature and in ocular healing processes. Technological advancements in instruments, in particular in vivo confocal microscopy and aethesiometry, have allowed for the structural and functional evaluation of corneal nerves in health and disease. Through application of these technologies in humans and animal models, structural and functional abnormalities have been detected in several ocular and systemic disorders, including dry eye disease (DED), glaucoma, migraine, and fibromyalgia. However, studies across a number of conditions have found that structural abnormalities do not always relate to functional abnormalities. This review will discuss instruments used to evaluate corneal nerves and summarize data on nerve abnormalities in a number of ocular and systemic conditions. Furthermore, it will discuss potential treatments that can alleviate the main manifestations of nerve dysfunction, namely ocular surface pain and persistent epithelial defects.
Development of lacrimal gland inflammation in the mouse model of herpes stromal keratitis
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Herpes stromal keratitis (HSK) is a chronic immunoinflammatory condition which develops in response to recurrent herpes simplex virus-1 (HSV-1) infection of the cornea. Patients with HSK often demonstrate the concurrence of corneal desiccation and the loss of blink reflex. However, the relationship between severity of HSK, level of basal tears and inflammation of the lacrimal gland is mostly unexplored. In this study, we compared these variables in extraorbital lacrimal gland (EoLG) after corneal HSV-1 infection in the C57BL/6J mouse model. Our results showed a significant reduction in the volume of tears in infected eyes during the development of HSK. Extensive architectural damage to EoLG, presumably caused by a massive influx of interferon-gamma secreting T cells, was observed during clinical disease period of HSK. A positive correlation between the decrease in tear volume, severity of HSK and the damage to EoLG were evident in infected mice. The presence of infectious virus measured in EoLG during pre-clinical, but not clinical disease period of HSK, suggested that viral cytopathic effects are not the major contributors of extensive damage seen in EoLG. Furthermore, topical administration of lacritin peptide delayed but did not prevent the decrease in tears in HSV-1 infected mice, and had no significant effect in either reducing the severity of HSK or T cell infiltration in EoLG of infected mice. Together, our results showed an interplay between the severity of HSK, inflammation of EoLG, and the reduced level of tears after corneal HSV-1 infection.

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ReviewImmunity causing blindness: five different paths to herpes stromal keratitis

Abstract

Clin. Immunol. Immunopathol.

Infect. Immun.

Invest. Ophthalmol. Vis. Sci.

Curr. Eye Res.

Ophthalmic Res.

J. Immunol.

J. Gen. Virol.

Br. j. Exp. Pathol.

Reg. Immunol.

Invest. Ophthalmol. Vis. Sci.

Invest. Ophthalmol. Vis. Sci.

Br. J. Ophthalmol.

Graefc's Arch. Clin. Exp. Ophthalmol.

Arch. Ophthalmol.

Curr. Eye Res.

J. Immunol.

Invest. Ophthalmol. Vis. Sci.

J. Immunol

J. Virol.

J. Immunol.

J. Immunol.

Invest. Ophthalmol. Vis. Sci.

J. Exp. Med.

Review
Immunity causing blindness: five different paths to herpes stromal keratitis