Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye.

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.

The pathogenic role of dendritic cells in non-infectious anterior uveitis.

BACKGROUND: Anterior uveitis (AU) is characterised by infiltration of immune cells into the anterior chamber of the eye. Dendritic cells (DC) are professional antigen presenting cells that initiate and promote inflammation. This study aims to characterise DC in AU and to examine the effects of aqueous humor (AqH) on DC maturation and function. METHODS: The frequency and phenotype of AU and healthy control (HC) circulating DC was examined. AU and HC AqH was immunostained and assessed by flow cytometry. The effect of AU and HC AqH on DC activation and maturation was examined and subsequent effects on CD4+ T cell proliferation assessed. RESULTS: AU peripheral blood demonstrated decreased circulating myeloid and plasmacytoid DC. Within AU AqH, three populations of CD45+ cells were significantly enriched compared to HC; DCs (CD11c+ HLA-DR+), neutrophils (CD15+ CD11c+) and T cells (CD4+ and CD8+). A significant increase in IFNγ, IL8 and IL6 was observed in the AU AqH, which was also significantly higher than that of paired serum. AU AqH induced expression of CD40 and CD80 on DC, which resulted in increased T cell proliferation and the production of GM-CSF, IFNγ and TNFα. CONCLUSION: DC are enriched at the site of inflammation in AU. Our data demonstrate an increase in inflammatory mediators in the AU inflamed microenvironment. AU AqH can activate DC, leading to subsequent proliferation and activation of effector T cells. Thus, the AU microenvironment contributes to immune cell responses and intraocular inflammation.

[Keratitis - Infectious or Autoimmune?]. / Keratitis - infektiös oder autoimmun?

Histopathological evaluation of ocular tissues is important in differentiating between infectious and autoimmune disease. Inflammation, necrosis and keratolysis are common to most forms of keratitis. Histopathology can be of great help in identifying the causative organism, establishing a final diagnosis and/or managing the patient with herpes simplex virus keratitis, mycotic keratitis, acanthamoeba keratitis or microsporidia keratoconjunctivitis. Important pathogenetic knowledge with therapeutic relevance has been gained from histopathological studies in nummular keratitis after epidemic keratoconjunctivitis and atopic keratoconjunctivitis.

[Intraocular Inflammation: Autoimmune or Infectious?]. / Intraokulare Entzündung: autoimmun oder infektiös?

Presentation of 3 cases of intraocular inflammation: 1. 47-year old female patient with severe necrotising scleritis and uveitis with underlying granulomatous polyangiitis (formerly known as Wegener granulomatosis, in honour of the German pathologist Friedrich Wegener), known for 10 years. 2. 48-year old male patient with longstanding bilateral uveitis and granulomatous polyangiitis for 2 years. In the histopathological examination of the enucleation specimen, a retrolental tumour turned out to be a granuloma. 3. 57-year old male patient in status post renal transplantation with intraocular cellular infiltration suspicious for lymphoma, which surprisingly proved to be Toxoplasma gondii-associated uveitis. The clinical course and characteristic histological signs and therapeutic options are discussed.

Degeneration and Regeneration of Subbasal Corneal Nerves after Infectious Keratitis: A Longitudinal In Vivo Confocal Microscopy Study.

PURPOSE: To investigate the longitudinal alterations of subbasal corneal nerves in patients with infectious keratitis (IK) during the acute phase, cessation of treatment, and the recovery phase by in vivo confocal microscopy (IVCM). DESIGN: Prospective, longitudinal, case-control, single-center study. PARTICIPANTS: Fifty-six eyes of 56 patients with the diagnosis of bacterial (n=28), fungal (n=15), or Acanthamoeba (n=13) keratitis were included in the study. Thirty eyes of 30 normal volunteers constituted the control group. METHODS: Corneal sensation and serial IVCM of the central cornea were performed prospectively using the Heidelberg Retina Tomograph 3/Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany). The IVCM images were assessed at 3 time points: at the acute phase (first visit to the cornea service), at cessation of antimicrobial treatment, and up to 6 months after the resolution of infection. MAIN OUTCOME MEASURES: Total nerve number and length, main nerve trunks, branching, and corneal sensation were assessed during the follow-up period. RESULTS: Corneal nerves were reduced significantly during the acute phase in eyes with IK compared with controls across all subgroups, with total nerve length of 5.47±0.69 mm/mm2 versus 20.59±1.06 mm/mm2 (P<0.0001). At the cessation of treatment, corneal nerves in patients with IK had regenerated, including total nerve length (8.49±0.94 mm/mm2; P=0.02) and nerve branch length (4.80±0.37 mm/mm2; P=0.005). During the recovery phase, after resolution of infection, corneal nerves regenerated further, including total nerve length (12.13±1.97 mm/mm2; P=0.005), main nerve trunk length (5.80±1.00 mm/mm2; P=0.01), and nerve branch length (6.33±0.76 mm/mm2; P=0.003) as compared with the acute phase, but were still significantly lower when compared with controls (P<0.05 for all parameters). Corneal degeneration and regeneration correlated with corneal sensation (r=0.47; P=0.0009). CONCLUSIONS: Patients with IK who sustain profound loss of corneal nerves during the acute phase of infection demonstrate increased corneal nerve density during the first 6 months after the resolution of infection. However, despite significant nerve regeneration, corneal nerve density does not recover fully and remains low compared to controls. By providing an objective methodology to monitor corneal re-innervation, IVCM adds potentially important findings that may have implications for clinical management and surgical planning.

Canine ocular protothecosis: A review of 14 cases.

PURPOSE: To examine a series of 14 cases of canine ocular protothecosis from archived cases from the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW), and compare gross and histologic findings. METHODS: Archival records from COPLOW were searched for canine cases of ocular protothecosis. Fourteen cases that contained matching criteria were identified, and gross and histologic findings, and clinical records for each case were tabulated, examined, and compared (2001-2013). RESULTS: Of the 14 cases identified, six had evidence of systemic disease, as per clinical history. Two of the 14 cases had Prototheca identified via cytology of ocular fluid or retinal exudate; in the remainder of cases, Prototheca identified via cytology of ocular fluid or retinal exudate in the remaining 12 cases, Prototheca was identified upon histologic examination of the submitted globe(s). Presenting ocular clinical signs were variable and nonspecific. Duration of ocular clinical signs varied from days to months. Fundoscopically, white membranes or plaques were identified on or around the retina in five cases. Retinal detachment was identified in 13 of the 14 submitted globes on gross examination following fixation and sectioning. The predominant histologic finding was granulomatous chorioretinitis with retinal detachment, with variable numbers of Prototheca within the inflammatory infiltrate. CONCLUSIONS: Due to the nonspecific nature of the ocular signs, a diagnosis of protothecosis generally is not made until enucleation and histopathologic examination of the globe(s). Retinal detachment and blindness were common. Cytologic sampling of retinal plaques and exudate may provide a rapid way to identify Prototheca.

Lagenidium sp. ocular infection mimicking ocular pythiosis.

This is a report of a Lagenidium sp. in a Thai patient who was diagnosed with severe keratitis that was unresponsive to antibacterial and antifungal drugs. Examination of a corneal biopsy specimen confirmed the presence of aseptate hyphae. The internal transcribed spacer DNA sequence of the strain isolated showed 97% identity with Lagenidium giganteum and other Lagenidium species.

Role of miR-132 in angiogenesis after ocular infection with herpes simplex virus.

MicroRNAs (miRNAs) are small regulatory molecules that control diverse biological processes that include angiogenesis. Herpes simplex virus (HSV) causes a chronic immuno-inflammatory response in the eye that may result in corneal neovascularization during blinding immunopathological lesion stromal keratitis (SK). miR-132 is a highly conserved miRNA that is induced in endothelial cells in response to growth factors, such as vascular endothelial growth factor (VEGF). In this study, we show that miR-132 expression was up-regulated (10- to 20-fold) after ocular infection with HSV, an event that involved the production of both VEGF-A and IL-17. Consequently, blockade of VEGF-A activity using soluble VEGF receptor 1 resulted in significantly lower levels of corneal miR-132 after HSV infection. In addition, low levels of corneal miR-132 were detected in IL-17 receptor knockout mice after HSV infection. In vivo silencing of miR-132 by the provision of anti-miR-132 (antagomir-132) nanoparticles to HSV-infected mice led to reduced corneal neovascularization and diminished SK lesions. The anti-angiogenic effect of antagomir-132 was reflected by a reduction in angiogenic Ras activity in corneal CD31-enriched cells (presumably blood vessel endothelial cells) during SK. To our knowledge, this is one of the first reports of miRNA involvement in an infectious ocular disease. Manipulating miRNA expression holds promise as a therapeutic approach to control an ocular lesion that is an important cause of human blindness.

Targeting toll-like receptor signaling as a novel approach to prevent ocular infectious diseases.

Toll-like receptors (TLRs) play a key role in the innate immune response to invading pathogens. Thus, their discovery has opened up a wide range of therapeutic possibilities for various infectious and inflammatory diseases. In the last several years, extensive research efforts have provided a considerable wealth of information on the expression and function of TLRs in the eye, with significant implications for better understanding of pathogenesis of infectious eye diseases affecting the cornea, uvea, and the retina. In this review, by using bacterial keratitis and endophthalmitis as examples, we discuss the possibilities of targeting TLR signaling for the prevention or treatment of ocular infectious diseases.

[Evaluation of chemokines in tears of patients with infectious keratitis].

PURPOSE: To investigate the chemokine profile in tears of patients with infectious keratitis. SUBJECTS AND METHODS: Subjects were 32 eyes of 16 patients with infectious keratitis and 5 eyes of 5 healthy volunteers as a control. The patients with infectious keratitis were classified into two groups of eyes: 10 with bacterial keratitis and 6 with Acanthamoeba keratitis. Tear fluid was obtained from both eyes of the patients with infectious keratitis and from the right eyes of the control subjects using filter paper. Chemokine concentration (unit: Odu/mm2) and its profile in tears was analyzed using an antibody-array. RESULTS: In terms of chemokine profile in the bacterial keratitis group, the expression volume of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in the diseased eyes was significantly higher than in the healthy eyes (p < 0.05). The expression volume of mucosae-associated epithelial chemokines (MECs) in the diseased eyes of the bacterial keratitis group was significantly lower than in the healthy eyes of that group (p < 0.05). In the Acanthamoeba keratitis group, chemokines were not significantly increased in the diseased eyes compared with those in the healthy eyes. However, MCP-1 was increased in tears of the Acanthamoeba keratitis group. Regarding the chemokine ratio, the IL-8/MEC ratio in the diseased eyes of the Pseudomonas keratitis group and the MCP-1/IL-8 in the diseased eyes of the Acanthamoeba keratitis group showed a significantly high level (p < 0.05). CONCLUSION: We concluded that the analyses of the chemokine profile and chemokine ratio in the tears of infectious keratitis patients is useful as a clinical tear laboratory test to interpret the pathologic condition of infectious keratitis

CD11c controls herpes simplex virus 1 responses to limit virus replication during primary infection.

CD11c is expressed on the surface of dendritic cells (DCs) and is one of the main markers for identification of DCs. DCs are the effectors of central innate immune responses, but they also affect acquired immune responses to infection. However, how DCs influence the efficacy of adaptive immunity is poorly understood. Here, we show that CD11c(+) DCs negatively orchestrate both adaptive and innate immunity against herpes simplex virus type 1 (HSV-1) ocular infection. The effectiveness and quantity of virus-specific CD8(+) T cell responses are increased in CD11c-deficient animals. In addition, the levels of CD83, CD11b, alpha interferon (IFN-α), and IFN-ß, but not IFN-γ, were significantly increased in CD11c-deficient animals. Higher levels of IFN-α, IFN-ß, and CD8(+) T cells in the CD11c-deficient mice may have contributed to lower virus replication in the eye and trigeminal ganglia (TG) during the early period of infection than in wild-type mice. However, the absence of CD11c did not influence survival, severity of eye disease, or latency. Our studies provide for the first time evidence that CD11c expression may abrogate the ability to reduce primary virus replication in the eye and TG via higher activities of type 1 interferon and CD8(+) T cell responses.

[Physical and chemical stability of fortified ophtalmic ready-to-use solutions: review of literature]. / Stabilité physico-chimique de solutions ophtalmiques renforcées prêtes à l'emploi : une revue de la littérature.

INTRODUCTION: Ophtalmic infections and inflammations are often encountered during hospitalization. They require the preparation of "fortified" ophtalmic solutions, i.e. pharmaceutical ophtalmic solutions which are hyperconcentrated in active substance. The data of physicochemical stabilities are modified and it is therefore essential to gather the results of the various publications devoted to this subject. METHOD: In 2006, an initial literature review was undertaken to identify the molecules mostly used in the preparation of fortified ophtalmic solutions in hospital. A second review of the literature in 2010 has enriched the knowledge about it. RESULTS: Two new drugs have entered the summary table: amikacin and ticarcillin disodium. Date on 12 molecules already known in 2006 were updated to improve clinical practices. A review of the literature was undertaken in order to collect the results of the molecules mostly used for the preparation of the fortified ophtalmic solutions in hospitals. A summary table, indicating the active substance, its concentration, the assay method, the storage temperature and physicochemical modifications, presents all the results. CONCLUSION: This review of literature makes it possible to match stability and validity period to these preparations.

The globe: infection, inflammation, and systemic disease.

Infection, inflammation, and systemic diseases affecting the globe encompass a broad range of pathologies which may ultimately lead to progressive vision loss. Clinical symptomatology varies from the inexorably silent progressive visual loss to an acute presentation of ocular pain and/or red eye. Most are diagnosed by clinical ophthalmologic examination with selective use of ultrasound, computed tomography, and magnetic resonance imaging for confirmation of the diagnosis, assessment of disease extent, and signs of associated systemic disease. Knowledge of the differential diagnoses of vision loss, ocular pain, and redness makes imaging analysis of this diverse group of processes more precise.

Two cases of human thelaziasis and brief review of Korean cases.

The present study was performed to describe 2 cases of human thelaziasis (HT) which occurred in Gyeongsangnam- do and to briefly review the previously reported Korean cases. A 58-year old woman, residing in Hadong-gun, Gyeongsangnam-do, came to Gyeongsang National University Hospital (GNUH) complaining of foreign body sensation and itching of the right eye in March 2000. Total 6 adult nematodes of Thelazia callipaeda (2 males and 4 females) were detected in her right eye. A 80-year old man, residing in Jinju-si, Gyeongsangnam-do, came to GNUH complaining of foreign body sensation, itching, and pain of the right eye in December 2007. A total of 5 worms (4 females and 1 degenerated) were removed from his right eye. We analyzed characteristics of the total 39 Korean HT cases reported to date, including the present 2 cases. Most of the cases (71.8%) occurred in Seoul and Gyeonggi-do before 2000, and 21 cases (53.8%) were males and 18 (46.2%) were females. The prevalence was higher in younger ages below 30 years (48.7%) than 31-60 years (41.0%) and over 61 years (10.3%). The seasonal prevalence showed a higher incidence in autumn (43.6%) than in other seasons. Most of the cases (94.9%) were conjunctival sac infections and only 2 (5.1%) were intraocular cases. The present 2 HT cases are the first reported cases in Gyeongsangnam-do. Some characteristics of Korean HT cases were analyzed.

The Epithelial Cell Glycocalyx in Ocular Surface Infection.

The glycocalyx is the main component of the transcellular barrier located at the interface between the ocular surface epithelia and the external environment. This barrier extends up to 500 nm from the plasma membrane and projects into the tear fluid bathing the surface of the eye. Under homeostatic conditions, defense molecules in the glycocalyx, such as transmembrane mucins, resist infection. However, many pathogenic microorganisms have evolved to exploit components of the glycocalyx in order to gain access to epithelial cells and consequently exert deleterious effects. This manuscript reviews the implications of the ocular surface epithelial glycocalyx to bacterial, viral, fungal and parasitic infection. Moreover, it presents some ongoing controversies surrounding the functional relevance of the epithelial glycocalyx to ocular infectious disease.

Ocular syphilis among HIV-infected individuals.

We describe a human immunodeficiency virus (HIV)-infected individual with ocular manifestations of secondary syphilis. Twelve other cases of HIV-associated ocular syphilis are also presented. Six of 12 individuals had normal cerebrospinal fluid study results, and 3 patients required retreatment within 1.5 years. In patients with HIV infection, clinicians should be vigilant for ocular syphilis despite normal cerebrospinal fluid measures and for syphilis reinfection.

Ocular infection of mice with an avirulent recombinant HSV-1 expressing IL-4 and an attenuated HSV-1 strain generates virulent recombinants in vivo.

PURPOSE: To assess the relative impact of overexpression of interleukin 2 (IL-2), interleukin 4 (IL-4), and interferon gamma (IFN-γ) expressing recombinant herpes simplex virus type 1 (HSV-1) on altering immune responses in ocularly infected mice. METHODS: BALB/c mice were co-infected ocularly with avirulent HSV-1 strain KOS and avirulent recombinant HSV-1 expressing murine IL-4 (HSV-IL-4). Controls mice were co-infected with KOS+HSV-IL-2 or KOS+HSV-IFNγ. Following ocular infection, virus replication in the eye, corneal scarring (CS), and survival were determined. We also isolated recombinant viruses from eye and trigeminal ganglia of KOS+HSV-IL-4 infected mice. RESULTS: In this study we found that ocular infection of BALB/c mice with a mixture of HSV-IL-4 and KOS resulted in increased death and increased eye disease. In contrast, when mice were infected in one eye with KOS and the other eye with HSV-IL-4 no death or eye disease was seen. Intraperitoneal co-infection of mice with KOS and HSV-IL-4 also did not result in HSV-1 induced death. Interestingly, ocular infection of mice with a mixture of HSV-IL-2 and KOS did not have any effect on severity of the disease in infected mice. We isolated recombinant viruses from KOS+HSV-IL-4 infected mice eye and trigeminal ganglia. Some of the isolated viruses were more neurovirulent then either parental virus. Infection of macrophages with IL-4 expressing virus down-regulated IL-12 production by macrophages. CONCLUSIONS: These results suggest a role for IL-4 in suppression of immune response and generation of virulent viruses in vivo.

Experimental oral and ocular Encephalitozoon cuniculi infection in rabbits.

Encephalitozoon cuniculi is an obligate intracellular pathogen that has a wide host distribution, but primarily affects rabbits. The aim of this study was to characterize both the cell-mediated and the antibody response in rabbits after experimental infection using 2 different infection routes: oral and ocular. SPF rabbits were infected with low (10³ spores) and high (107 spores) infection doses. Monitored parameters included clinical signs, detection of spores in urine, antibody response detected with ELISA, and cell-mediated immunity detected by antigen-driven lymphocyte proliferation. At week 13 post-infection, half of the rabbits in each group were suppressed by intramuscular administration of dexamethasone. At week 18 post-infection, animals were euthanized. Clinical signs were mild with exacerbation after immunosuppression. Spores in urine and antigen-specific cell-mediated immunity were detected from weeks 5 and 4 post-infection, respectively. Specific IgM was detected 1 week after infection, and IgG antibodies followed 1 week later in rabbits infected with the high dose. Immunological responses were dose dependent. The authors can conclude that both oral and ocular experimental infection with E. cuniculi resulted in an immune response of the infected animals. Rabbits could be used as an experimental model for the study of ocular microsporidiosis.

[Quantitative evaluation of infectious keratitis by anterior segment optical coherence tomography]. / Évaluation quantitative des kératites infectieuses par tomographie en cohérence optique du segment antérieur.

The clinical evaluation of infectious keratitis takes place largely through biomicroscopic examination, which presents limitations in the evaluation of the depth of the infiltrate and the exact thickness of the cornea, whether edematous or thinned. In this study, we aim to quantify the human corneal inflammatory response in treated infectious keratitis by anterior segment optical coherence tomography (AS-OCT). Patients with infectious keratitis were recruited prospectively in the ophthalmology department of the military hospital of Rabat between November 2017 and May 2019. Over the study period, 32 patients were included. A standardized scanning protocol was used. The thickness of the infiltrate, when present, and corneal thickness in any area of thinning and any surrounding edematous areas were measured. The various thicknesses gradually decreased over the course of follow-up, providing objective evidence of therapeutic efficacy in the early stages. Improvement in corneal edema and thinning was faster in the early stage. AS-OCT scanning can be used along with slit lamp examination to quantify and objectively follow infectious keratitis.

[Panorama of limbal alterations (French translation of the article)]. / Panorama des altérations limbiques cornéennes.

The corneal limbus is a privileged region on the border between two quite different microenvironments, where corneal epithelial stem cells, numerous melanocytes, and antigen-presenting cells are all concentrated within a richly vascularized and innervated stroma. This situation within the ocular surface confers on it the key functions of barrier, epithelial renewal and defense of the cornea. As an immunological crossroads and since the corneoscleral limbus is directly exposed to external insults such as caustic agents, ultraviolet radiation, microbial agents, and allergens, it is the potential site of many tumoral, degenerative or inflammatory pathologies and may progress under certain conditions to limbal stem cell deficiency.