Early inhibition of nitric oxide production increases HSV‐1 intranasal infection

Gamba, Gisela; Cavalieri, Hernan; Courrèges, Marı́a C.; Massouh, Ernesto; Benencia, Fabián

doi:10.1002/jmv.20093

Cited by 28 publications

(21 citation statements)

References 67 publications

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“…IL-12, in synergy with IFN-α/β, can enhance the production of IFN-γ by NK cells (Hunter et al, 1997). IFN-γ released by NK cells subsequently activates macrophages to produce inducible nitric oxide synthase (iNOS), which produces NO to limit HSV replication (Croen, 1993; Gamba et al, 2004). …”

Section: Immune Control Of Primary Corneal Infectionmentioning

confidence: 99%

Herpes keratitis

Rowe

Leger

Jeon

et al. 2013

Progress in Retinal and Eye Research

260

235

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Herpes Simplex Virus-1 (HSV-1) infects the majority of the world’s population. These infections are often asymptomatic, but ocular HSV-1 infections cause multiple pathologies with perhaps the most destructive being Herpes Stromal Keratitis (HSK). HSK lesions, which are immunoinflammatory in nature, can recur throughout life and often cause progressive corneal scaring resulting in visual impairment. Current treatment involves broad local immunosuppression with topical steroids along with antiviral coverage. Unfortunately, the immunopathologic mechanisms defined in animal models of HSK have not yet translated into improved therapy. Herein, we review the clinical epidemiology and pathology of the disease and summarize the large amount of basic research regarding the immunopathology of HSK. We examine the role of the innate and adaptive immune system in the clearance of virus and the destruction of the normal corneal architecture that is typical of HSK. Our goal is to define current knowledge of the pathogenic mechanisms and recurrent nature of HSK and identify areas that require further study.

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Section: Immune Control Of Primary Corneal Infectionmentioning

confidence: 99%

Herpes keratitis

Rowe

Leger

Jeon

et al. 2013

Progress in Retinal and Eye Research

260

235

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“…NO is a product of the cellular immune system that is well known as a reactive free radical molecule that modulates cytokine expression, and it is beneficial to the host defense against virus infections (61). For example, cells with iNOS inhibited by 1-NG-monomethyl arginine (1-NMMA) failed to restrict Japanese encephalitis virus (JEV) replication (62), and IFN-␥-induced iNOS and NO production inhibited the replication of vaccinia virus (VV) and HSV-1 (17,63). Our observations implicating NO in resistance to HIV-1 are consistent with this.…”

Section: Discussionmentioning

confidence: 99%

“…Early inhibition of NO by i.n. administration of aminoguanidine (AG) was found to increase HSV-1 infection in the eyes and lungs of mice (17). Conversely, pretreatment with an NO donor, sodium nitroprusside (SNP), decreased the titer of Sindbis virus (18).…”

mentioning

confidence: 99%

Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1

Geng

et al. 2015

Clin Vaccine Immunol

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Caveolin-1 (Cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. Several viruses exploit caveolae to facilitate viral infections. However, the roles of Cav-1 in herpes simplex virus 1 (HSV-1) infection have not fully been elucidated. Here, we report that Cav-1 downregulates the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in dendritic cells (DCs) during HSV-1 infection. As a result, Cav-1 deficiency led to an accelerated elimination of virus and less lung pathological change following HSV-1 infection. This protection was dependent on iNOS and NO production in DCs. Adoptive transfer of DCs with Cav-1 knockdown was sufficient to confer the protection to wild-type (WT) mice. In addition, Cav-1 knockout (KO) (Cav-1 ؊/؊ ) mice treated with an iNOS inhibitor exhibited significantly reduced survival compared to that of the nontreated controls. We found that Cav-1 colocalized with iNOS and HSV-1 in caveolae in HSV-1-infected DCs, suggesting their interaction. Taken together, our results identified Cav-1 as a novel regulator utilized by HSV-1 to evade the host antiviral response mediated by NO production. Therefore, Cav-1 might be a valuable target for therapeutic approaches against herpesvirus infections. Herpes simplex virus 1 (HSV-1) is a double-stranded DNA (dsDNA) virus belonging to the Alphaherpesvirus family, which causes oral herpes, encephalitis, keratitis, neonatal herpes, and pneumonia disease, establishing latency in the neurons after acute infection of mucosal tissues (1-3). Notably, HSV-1 can be isolated from the respiratory tract of immunosuppressed patients and newborn infants, where it induces pneumonitis, resulting in remarkable morbidity and mortality (4). Recent studies have suggested that HSV-1-induced bronchopneumonitis is common in nonimmunocompromised persons who are undergoing continuous mechanical ventilation (5). Currently, the mechanisms of HSV-1-induced pneumonia and obstructive pulmonary disease are not fully understood, although intranasal (i.n.) infection with HSV-1 in mice can be used as a model to investigate these mechanisms (4, 6, 7). Such investigations might reveal a valuable therapeutic approach for HSV-1-induced pneumonia.Innate defense cells and inflammatory factors serve as the firstline of host defense against viral infections. DCs can be recruited to the lungs and in the cornea of the eye, where they contribute to host defense (8, 9). Studies have shown that diphtheria toxin (DT)-induced depletion of DCs in CD11c-DTR mice (in which the DT receptor [DTR] is expressed under the control of the CD11c promoter) inhibited the migration of natural killer cells and neutrophils to locally infected cornea, resulting in severe pathology (10, 11). Moreover, involvement of the free radical nitric oxide (NO) has been indicated. This is a powerful vasodilator factor and cell signaling molecule, with a short half-life of 3 to ϳ4 s in the blood, and it is synthesized by nitric oxide s...

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“…On the one hand, Fujii et al [13] reported that inhibition of NOS by the nonselective NOS inhibitor L -NG-monomethyl arginine citrate several days after nasal inoculation of HSV-1 led to a significant amelioration of encephalitis, suggesting that high levels of NO produced by iNOS are a pathogenic factor in HSV-1 encephalitis. On the other hand, Gamba et al [17] showed that early administration of the selective iNOS inhibitor facilitated HSV-1 infection and increased the inflammatory process. In accordance with the latter finding, our results may suggest that the reduction in cNOS activity in the brain during the early stages of the viral infection could be one mechanism that facilitates HSV-1 infectivity.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that NOS activity may be involved in the early stages of the viral infection. It should be noted that in all previous reports, only the response of iNOS to HSV-1 was examined [13,14,16,17] . In view of the above, we were interested in examining both iNOS and constitutive NOS (cNOS) activity in different parts of the brain and in cultured glial cells during the early stages of HSV-1 infection.…”

mentioning

confidence: 99%

The Effect of Herpes Simplex Virus-1 on Nitric Oxide Synthase in the Rat Brain: The Role of Glucocorticoids

Hasson

Weidenfeld²,

Mizrachi-Kol³

et al. 2010

Neuroimmunomodulation

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Objective: Herpes simplex virus-1 (HSV-1) is a common cause of viral encephalitis manifested by activation of the adrenocortical axis, fever and behavioral changes. We investigated the early effects of HSV-1 on constitutive (c) and inducible (i) nitric oxide synthase (NOS) activity in rat brain and in mixed glial cell culture. The effect of glucocorticoids (GCs) on NOS responses to HSV-1 was also determined. Methods: NOS activity was evaluated by the conversion of ³H-arginine to ³H-citrulline. Nitrites were measured in supernatants of activated glial cells. Results: Under basal conditions, the highest cNOS activity was found in the cerebellum, while activity was much lower in the pons and negligible in the hypothalamus and hippocampus. Forty-eight hours after intracerebral injection of HSV-1, serum corticosterone was increased and NOS activity in the cerebellum and pons was inhibited. Adrenalectomy had no effect on the basal NOS activity but completely abrogated the inhibitory effect of HSV-1. Administration of the iNOS inhibitor aminoguanidine did not significantly change NOS activity, suggesting that the activity found in the cerebellum and pons can be attributed to the cNOS isoform. In mixed glial cell culture infected with HSV-1 and then activated with lipopolysaccharide, NOS activity and nitrite production were inhibited by 77 and 53%, respectively. Conclusions: These results suggest that brain NOS activity is inhibited in the early stages of HSV-1 infection and requires the presence of circulating GCs. HSV-1-induced brain NOS inhibition may play a role in neuronal viral invasion and in the activation of the adrenocortical axis.

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Early inhibition of nitric oxide production increases HSV‐1 intranasal infection

Cited by 28 publications

References 67 publications

Herpes keratitis

Herpes keratitis

Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1

The Effect of Herpes Simplex Virus-1 on Nitric Oxide Synthase in the Rat Brain: The Role of Glucocorticoids

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