scholarly journals Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

2014 ◽  
Vol 88 (14) ◽  
pp. 7870-7880 ◽  
Author(s):  
Hongmin Yun ◽  
Alexander M. Rowe ◽  
Kira L. Lathrop ◽  
Stephen A. K. Harvey ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Mouse Model ◽  
Human Disease ◽  
Sensory Nerve ◽  
Blink Reflex ◽  
Nerve Damage ◽  
Corneal Scarring ◽  
Corneal Nerves ◽  
Stromal Keratitis

ABSTRACTHerpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4+T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted.IMPORTANCEHSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4+T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease.

scholarly journals Complement and CD4+ T cells drive context-specific corneal sensory neuropathy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Derek J Royer ◽  
Jose Echegaray-Mendez ◽  
Liwen Lin ◽  
Grzegorz B Gmyrek ◽  
Rose Mathew ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Cd4 T Cells ◽  
Sensory Nerve ◽  
Sensory Neuropathy ◽  
Nerve Damage ◽  
Cd4 T Cell ◽  
Peripheral Nervous System Diseases ◽  
Cell Axis

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies.

scholarly journals Identification and Characterization of Herpes Simplex Virus‐Specific CD4+T Cells in Corneas of Herpetic Stromal Keratitis Patients

1998 ◽  
Vol 177 (2) ◽  
pp. 484-488 ◽  
Author(s):  
Georges M. G. M. Verjans ◽  
Lies Remeijer ◽  
Robert S. van Binnendijk ◽  
José G. C. Cornelissen ◽  
Hennie J. Völker‐Dieben ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cd4 T Cells ◽  
Herpetic Stromal Keratitis ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Identification And Characterization

scholarly journals CD80 Plays a Critical Role in Increased Inflammatory Responses in Herpes Simplex Virus 1-Infected Mouse Corneas

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Kati Tormanen ◽  
Shaohui Wang ◽  
Homayon Ghiasi
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Parental Virus ◽  
Eye Disease ◽  
Herpes Simplex Virus 1 ◽  
Corneal Scarring ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT We recently reported that herpes simplex virus 1 (HSV-1) infection suppresses CD80 but not CD86 expression in vitro and in vivo. This suppression required the HSV-1 ICP22 gene. We also reported that overexpression of CD80 by HSV-1 exacerbated corneal scarring in BALB/c mice. We now show that this recombinant virus (HSV-CD80) expressed high levels of CD80 both in vitro in cultured rabbit skin cells and in vivo in infected mouse corneas. CD80 protein was detected on the surface of infected cells. The virulence of the recombinant HSV-CD80 virus was similar to that of the parental strain, and the replication of HSV-CD80 was similar to that of control virus in vitro and in vivo. Transcriptome analysis detected 75 known HSV-1 genes in the corneas of mice infected with HSV-CD80 or parental virus on day 4 postinfection. Except for significantly higher CD80 expression in HSV-CD80-infected mice, levels of HSV-1 gene expression were similar in corneas from HSV-CD80-infected and parental virus-infected mice. The number of CD8+ T cells was higher, and the number of CD4+ T cells was lower, in the corneas of HSV-CD80-infected mice than in mice infected with parental virus. HSV-CD80-infected mice displayed a transient increase in dendritic cells. Transcriptome analysis revealed mild differences in dendritic cell maturation and interleukin-1 signaling pathways and increased expression of interferon-induced protein with tetratricopeptide repeats 2 (Ifit2). Together, these results suggest that increased CD80 levels promote increased CD8+ T cells, leading to exacerbated eye disease in HSV-1-infected mice. IMPORTANCE HSV-1 ocular infections are the leading cause of corneal blindness. Eye disease is the result of a prolonged immune response to the replicating virus. HSV-1, on the other hand, has evolved several mechanisms to evade clearance by the host immune system. We describe a novel mechanism of HSV-1 immune evasion via ICP22-dependent downregulation of the host T cell costimulatory molecule CD80. However, the exact role of CD80 in HSV-1 immune pathology is not clear. In this study, we show that eye disease is independent of the level of HSV-1 replication and that viral expression of CD80 has a detrimental role in corneal scarring, likely by increasing CD8+ T cell recruitment and activation.

scholarly journals Level of Herpes Simplex Virus Type 1 Latency Correlates with Severity of Corneal Scarring and Exhaustion of CD8+ T Cells in Trigeminal Ganglia of Latently Infected Mice

2008 ◽  
Vol 83 (5) ◽  
pp. 2246-2254 ◽  
Author(s):  
Kevin R. Mott ◽  
Catherine J. Bresee ◽  
Sariah J. Allen ◽  
Lbachir BenMohamed ◽  
Steven L. Wechsler ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Individual ◽  
Trigeminal Ganglia ◽  
Corneal Scarring ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT A hallmark of infection with herpes simplex virus type 1 (HSV-1) is the establishment of latency in ganglia of the infected individual. During the life of the latently infected individual, the virus can occasionally reactivate, travel back to the eye, and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) is the scarring induced by HSV-1 following reactivation from latency. In this study, we evaluated the relationship between the amount of CS and the level of the HSV-1 latency-associated transcript (LAT) in trigeminal ganglia (TG) of latently infected mice. Our results suggested that the amount of CS was not related to the amount of virus replication following primary ocular HSV-1 infection, since replication in the eyes was similar in mice that did not develop CS, mice that developed CS in just one eye, and mice that developed CS in both eyes. In contrast, mice with no CS had significantly less LAT, and thus presumably less latency, in their TG than mice that had CS in both eyes. Higher CS also correlated with higher levels of mRNAs for PD-1, CD4, CD8, F4/80, interleukin-4, gamma interferon, granzyme A, and granzyme B in both cornea and TG. These results suggest that (i) the immunopathology induced by HSV-1 infection does not correlate with primary virus replication in the eye; (ii) increased CS appears to correlate with increased latency in the TG, although the possible cause-and-effect relationship is not known; and (iii) increased latency in mouse TG correlates with higher levels of PD-1 mRNA, suggesting exhaustion of CD8+ T cells.

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 Reactivation of herpes simplex keratitis following vaccination for COVID-19

2021 ◽  
Vol 14 (9) ◽  
pp. e245792
Author(s):  
James Richardson-May ◽  
Alice Rothwell ◽  
Mohammed Rashid
Keyword(s):  
Visual Acuity ◽  
Herpes Simplex ◽  
Eye Disease ◽  
Personal Health ◽  
Herpetic Stromal Keratitis ◽  
Corneal Scarring ◽  
History Of ◽  
Stromal Keratitis ◽  
Herpes Simplex Keratitis ◽  
Prompt Diagnosis

An 82-year-old man with a history of herpes simplex keratitis 40 years previously presented with recurrence, 1 day following vaccination for novel COVID-19. His condition worsened despite topical treatment with ganciclovir gel. A diagnosis of herpetic stromal keratitis was made, requiring systemic aciclovir, topical prednisolone, moxifloxacin and atropine, and oral doxycycline. He improved clinically on treatment, with some residual corneal scarring. Visual acuity improved from 6/36 corrected at presentation, to 6/24 following treatment. Clearly, public and personal health benefits from vaccination are hugely important and we would not suggest avoiding vaccination in such patients. It is, however, important for ophthalmic providers to be aware of the rare potential for reactivation of herpetic eye disease following vaccination to enable prompt diagnosis and treatment.

scholarly journals The Vaginal Acquisition and Dissemination of HIV-1 Infection in a Novel Transgenic Mouse Model Is Facilitated by Coinfection with Herpes Simplex Virus 2 and Is Inhibited by Microbicide Treatment

2015 ◽  
Vol 89 (18) ◽  
pp. 9559-9570 ◽  
Author(s):  
Kieran Seay ◽  
Nazanin Khajoueinejad ◽  
Jian Hua Zheng ◽  
Patrick Kiser ◽  
Christina Ochsenbauer ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mouse Model ◽  
Genital Tract ◽  
Epidemiological Studies ◽  
Preexposure Prophylaxis ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Hiv 1

ABSTRACTEpidemiological studies have demonstrated that herpes simplex virus 2 (HSV-2) infection significantly increases the risk of HIV-1 acquisition, thereby contributing to the expanding HIV-1 epidemic. To investigate whether HSV-2 infection directly facilitates mucosal HIV-1 acquisition, we used our transgenic hCD4/R5/cT1 mouse model which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5, and cyclin T1 genes to CD4+T cells and myeloid-committed cells. Productive infection of mucosal leukocytes, predominantly CD4+T cells, was detected in all hCD4/R5/cT1 mice intravaginally challenged with an HIV-1 infectious molecular clone, HIV-Du151.2env-NLuc, which expresses anenvgene (C.Du151.2) cloned from an acute heterosexually infected woman and a NanoLuc luciferase reporter gene. Lower genital tract HIV-1 infection after HIV-Du151.2env-NLuc intravaginal challenge was increased ∼4-fold in hCD4/R5/cT1 mice coinfected with HSV-2. Furthermore, HIV-1 dissemination to draining lymph nodes was detected only in HSV-2-coinfected mice. HSV-2 infection stimulated local infiltration and activation of CD4+T cells and dendritic cells, likely contributing to the enhanced HIV-1 infection and dissemination in HSV-2-coinfected mice. We then used this model to demonstrate that a novel gel containing tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), but not the TFV microbicide gel utilized in the recent CAPRISA 004, VOICE (Vaginal and Oral Interventions to Control the Epidemic), and FACTS 001 clinical trials, was effective as preexposure prophylaxis (PrEP) to completely prevent vaginal HIV-1 infection in almost half of HSV-2-coinfected mice. These results also support utilization of hCD4/R5/cT1 mice as a highly reproducible immunocompetent preclinical model to evaluate HIV-1 acquisition across the female genital tract.IMPORTANCEMultiple epidemiological studies have reported that genital herpes simplex virus 2 (HSV-2) infection increases the risk of HIV-1 sexual acquisition by severalfold. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. Using our novel transgenic hCD4/R5/cT1 mouse model infectible with HIV-1, we demonstrated that HSV-2 infection enhances vaginal transmission and dissemination of HIV-1 infection while stimulating recruitment and activation of CD4+T cells and dendritic cells in the lower genital tract. HIV acquisition by hCD4/R5/cT1 mice vaginally coinfected with HSV-2 could be completely prevented in almost half the mice by preexposure prophylaxis (PrEP) with a novel gel containing tenofovir disoproxil fumarate (TDF), the tenofovir prodrug, but not with the tenofovir microbicide gel utilized in CAPRISA-004, VOICE, and FACTS-001 clinical trials. The hCD4/R5/cT1 mice represent a new preclinical mouse model to evaluate vaginal HIV-1 acquisition.

scholarly journals Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Yike Jiang ◽  
Xiaotang Yin ◽  
Patrick M. Stuart ◽  
David A. Leib
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Herpetic Stromal Keratitis ◽  
Stromal Keratitis ◽  
Simplex Virus

ABSTRACTHerpetic stromal keratitis (HSK) is a blinding ocular disease that is initiated by HSV-1 and characterized by chronic inflammation in the cornea. Although HSK immunopathology of the cornea is well documented in animal models, events preceding this abnormal inflammatory cascade are poorly understood. In this study, we have examined the activation of pathological CD4+T cells in the development of HSK. Dendritic cell autophagy (DC-autophagy) is an important pathway regulating major histocompatibility complex class II (MHCII)-dependent antigen presentation and proper CD4+T cell activation during infectious diseases. Using DC-autophagy-deficient mice, we found that DC-autophagy significantly and specifically contributes to HSK disease without impacting early innate immune infiltration, viral clearance, or host survival. Instead, the observed phenotype was attributable to the abrogated activation of CD4+T cells and reduced inflammation in HSK lesions. We conclude that DC-autophagy is an important contributor to primary HSK immunopathology upstream of CD4+T cell activation.IMPORTANCEHerpetic stromal keratitis (HSK) is the leading cause of infectious blindness in the United States and a rising cause worldwide. HSK is induced by herpes simplex virus 1 but is considered a disease of inappropriately sustained inflammation driven by CD4+T cells. In this study, we investigated whether pathways preceding CD4+T cell activation affect disease outcome. We found that autophagy in dendritic cells significantly contributed to the incidence of HSK. Dendritic cell autophagy did not alter immune control of the virus or neurological disease but specifically augmented CD4+T cell activation and pathological corneal inflammation. This study broadens our understanding of the immunopathology that drives HSK and implicates the autophagy pathway as a new target for therapeutic intervention against this incurable form of infectious blindness.

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