Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.

Acute retinal necrosis in a patient with remote severe herpes simplex encephalitis.

A 60-year-old man with a history of severe herpes simplex virus type 1 (HSV-1) encephalitis 2 years prior presented with acute onset of visual loss in the left eye. Dilated funduscopic examination showed retinitis and occlusive vasculitis with retinal necrosis. PCR of the vitreous fluid was positive for HSV-1, and he was diagnosed with acute retinal necrosis (ARN) due to HSV-1. The patient was treated with intravenous acyclovir and intravitreous foscarnet for 2 weeks, followed by high dose oral valacyclovir for 2 weeks. He was subsequently placed on planned life-long suppressive valacyclovir. His case demonstrates that acute visual loss concomitant with or subsequent to HSV-1 encephalitis warrants suspicion of ARN. Prompt therapy with effective antiviral medication is necessary to reduce the risk of sight-threatening complications. Chronic suppression with oral antiviral therapy after ARN is recommended to prevent involvement of the contralateral eye, though there is no consensus on the duration and dosage of antivirals.

[Diagnostic and therapeutic strategy for acyclovir-resistant herpes encephalitis].

Acyclovir (ACV), which inhibits the replication of herpes simplex virus, is the standard drug for the treatment of herpes simplex encephalitis. Thanks to the introduction of ACV, the morbidity and mortality of HSE patients have significantly improved. However, the disease is still the severe infection, because it makes some patients with HSE suffer from severe consequences. The sensitivity test of the etiological HSV to ACV is very difficult due to the inability of isolation of the virus from cerebrospinal fluid (CSF). The cases of the ACV treatment-resistant HSE patients have been reported. However, these cases were not virologically confirmed. The first case of encephalitis in newborn baby with HSE caused by an ACV-resistant HSV-1, which was virologically confirmed, was reported by our group. According to the sensitivity profile of the causative viruses to antiviral drugs, the drugs of choice for HSE should be properly considered. Strategy for diagnoses of HSE including antiviral sensitivity assessment and selection of drugs in HSE is reviewed.

Herpes simplex virus encephalitis involving the right thalamus.

Herpes simplex virus (HSV) encephalitis is a rare but often fatal disease if left untreated. A 50-year-old woman was admitted with lethargy, confusion, dysphasia and cough. MRI brain demonstrated bilateral temporal and perisylvian hyperintense signal abnormality extending into the cingulate gyrus, typical of HSV encephalitis. However, there was also signal abnormality involving the right thalamus, indicating thalamic involvement. EEG and cerebrospinal fluid PCR confirmed HSV encephalitis. The patient was started on intravenous acyclovir resulting in marked improvement. Adequate assessment and prompt treatment of HSV encephalitis will aid in achieving adequate recovery. Radiological investigation plays a crucial role in diagnosis with typical MR features a useful aid to diagnosis. HSV encephalitis classically involves the medial temporal lobes, insula and cingulated gyri. The basal ganglia and thalami are nearly always spared. We present a very rare case of HSV encephalitis which involved the right thalamus.

[Herpes simplex encephalitis originating from bilateral thalamic lesions with hemorrhagic component].

A 71-year-old woman with hypertension and hypothyroidism was transferred to our hospital from a nearby hospital because of right thalamic hemorrhage evident on CT. She had been suffered from fever and headache for five days. Neurological examination on admission revealed somnolence, rigidity in the neck and extremities, and bilateral Babinski signs. Then she developed decorticate rigidity in a day. On brain MRI four hours after admission, T2-hyperintese lesions were demonstrated in the bilateral thalamus in addition to hemorrhagic change of the right thalamus on the initial CT. No pleocytosis was evident on cerebrospinal fluid examination at admission. Follow-up MRI on the fifth hospital day, however, revealed expansion of the lesions bilaterally to the medial temporal lobes including amygdala, hippocampus and insular cortex. The diagnosis of herpes simplex encephalitis was established by PCR of cerebrospinal fluid on the same day. After immediate treatment with acyclovir and ara-A, she gradually became conscious and could respond to simple conversation. This was an unusual case of herpes simplex encephalitis originating from bilateral thalamic lesions on brain imaging. We should consider thalamus as a primary lesion in herpes simplex encephalitis.

[Atypical encephalitis in a 20-year-old soldier]. / Atypische Enzephalitis eines 20-jährigen Wehrpflichtigen.

We report a patient with encephalitis who had been diagnosed with an unspecific aetiology. During follow-up, pneumonia was identified due to Mycoplasma pneumoniae infection that could also be confirmed as causal for the brain inflammation. Despite the initially critical clinical situation, the patient's condition improved under specific antibiotic treatment. Pathophysiologic, differential diagnostic, and therapeutic implications are discussed, and guidelines for diagnosis are proposed.