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Nature Microbiology Jul 2023Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with...
Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with antiviral acyclovir treatment, most patients still experience various neurological sequelae. Here we characterize HSV-1 infection of human brain organoids by combining single-cell RNA sequencing, electrophysiology and immunostaining. We observed strong perturbations of tissue integrity, neuronal function and cellular transcriptomes. Under acyclovir treatment viral replication was stopped, but did not prevent HSV-1-driven defects such as damage of neuronal processes and neuroepithelium. Unbiased analysis of pathways deregulated upon infection revealed tumour necrosis factor activation as a potential causal factor. Combination of anti-inflammatory drugs such as necrostatin-1 or bardoxolone methyl with antiviral treatment prevented the damages caused by infection, indicating that tuning the inflammatory response in acute infection may improve current therapeutic strategies.
Topics: Humans; Herpesvirus 1, Human; Herpes Simplex; Acyclovir; Antiviral Agents; Encephalitis, Viral; Organoids
PubMed: 37349587
DOI: 10.1038/s41564-023-01405-y -
European Respiratory Review : An... Sep 2023Exacerbations of COPD are associated with worsening of the airflow obstruction, hospitalisation, reduced quality of life, disease progression and death. At least 70% of...
Exacerbations of COPD are associated with worsening of the airflow obstruction, hospitalisation, reduced quality of life, disease progression and death. At least 70% of COPD exacerbations are infectious in origin, with respiratory viruses identified in approximately 30% of cases. Despite long-standing recommendations to vaccinate patients with COPD, vaccination rates remain suboptimal in this population. is one of the leading morbidity and mortality causes of lower respiratory tract infections. The Food and Drug Administration recently approved pneumococcal conjugate vaccines that showed strong immunogenicity against all 20 included serotypes. Influenza is the second most common virus linked to severe acute exacerbations of COPD. The variable vaccine efficacy across virus subtypes and the impaired immune response are significant drawbacks in the influenza vaccination strategy. High-dose and adjuvant vaccines are new approaches to tackle these problems. Respiratory syncytial virus is another virus known to cause acute exacerbations of COPD. The vaccine candidate RSVPreF3 is the first authorised for the prevention of RSV in adults ≥60 years and might help to reduce acute exacerbations of COPD. The 2023 Global Initiative for Chronic Lung Disease report recommends zoster vaccination to protect against shingles for people with COPD over 50 years.
Topics: Humans; COVID-19; Herpesvirus 3, Human; Influenza Vaccines; Influenza, Human; Quality of Life; SARS-CoV-2; Streptococcus pneumoniae; United States; Vaccination; Whooping Cough; Middle Aged; Aged
PubMed: 37673427
DOI: 10.1183/16000617.0034-2023 -
CMAJ : Canadian Medical Association... Jul 2023
Topics: Humans; Herpesvirus 2, Human; Acyclovir; Herpes Simplex; Immunocompromised Host
PubMed: 37429625
DOI: 10.1503/cmaj.221481-f -
BMJ (Clinical Research Ed.) Nov 2023To assess the effectiveness of live zoster vaccine during more than 10 years after vaccination; and to describe methods for ascertaining vaccine effectiveness in the...
OBJECTIVES
To assess the effectiveness of live zoster vaccine during more than 10 years after vaccination; and to describe methods for ascertaining vaccine effectiveness in the context of waning.
DESIGN
Real world cohort study using electronic health records.
SETTING
Kaiser Permanente Northern California, an integrated healthcare delivery system in the US, 1 January 2007 to 31 December 2018.
POPULATION
More than 1.5 million people aged 50 years and older followed for almost 9.4 million person years.
MAIN OUTCOME MEASURE
Vaccine effectiveness in preventing herpes zoster, postherpetic neuralgia, herpes zoster ophthalmicus, and admission to hospital for herpes zoster was assessed. Change in vaccine effectiveness by time since vaccination was examined using Cox regression with a calendar timeline. Time varying indicators were specified for each interval of time since vaccination (30 days to less than one year, one to less than two years, etc) and adjusted for covariates.
RESULTS
Of 1 505 647 people, 507 444 (34%) were vaccinated with live zoster vaccine. Among 75 135 incident herpes zoster cases, 4982 (7%) developed postherpetic neuralgia, 4439 (6%) had herpes zoster ophthalmicus, and 556 (0.7%) were admitted to hospital for herpes zoster. For each outcome, vaccine effectiveness was highest in the first year after vaccination and decreased substantially over time. Against herpes zoster, vaccine effectiveness waned from 67% (95% confidence interval 65% to 69%) in the first year to 15% (5% to 24%) after 10 years. Against postherpetic neuralgia, vaccine effectiveness waned from 83% (78% to 87%) to 41% (17% to 59%) after 10 years. Against herpes zoster ophthalmicus, vaccine effectiveness waned from 71% (63% to 76%) to 29% (18% to 39%) during five to less than eight years. Against admission to hospital for herpes zoster, vaccine effectiveness waned from 90% (67% to 97%) to 53% (25% to 70%) during five to less than eight years. Across all follow-up time, overall vaccine effectiveness was 46% (45% to 47%) against herpes zoster, 62% (59% to 65%) against postherpetic neuralgia, 45% (40% to 49%) against herpes zoster ophthalmicus, and 66% (55% to 74%) against admission to hospital for herpes zoster.
CONCLUSIONS
Live zoster vaccine was effective initially. Vaccine effectiveness waned substantially yet some protection remained 10 years after vaccination. After 10 years, protection was low against herpes zoster but higher against postherpetic neuralgia.
TRIAL REGISTRATION
ClinicalTrials.gov number NCT01600079; EU PAS register number EUPAS17502.
Topics: Humans; Middle Aged; Aged; Herpes Zoster Vaccine; Neuralgia, Postherpetic; Cohort Studies; Herpes Zoster Ophthalmicus; Electronic Health Records; Herpes Zoster; Herpesvirus 3, Human; Vaccination
PubMed: 37940142
DOI: 10.1136/bmj-2023-076321 -
Nucleic Acids Research Jul 2023The interferon inducible protein 16 (IFI16) is a prominent sensor of nuclear pathogenic DNA, initiating innate immune signaling and suppressing viral transcription....
The interferon inducible protein 16 (IFI16) is a prominent sensor of nuclear pathogenic DNA, initiating innate immune signaling and suppressing viral transcription. However, little is known about mechanisms that initiate IFI16 antiviral functions or its regulation within the host DNA-filled nucleus. Here, we provide in vitro and in vivo evidence to establish that IFI16 undergoes liquid-liquid phase separation (LLPS) nucleated by DNA. IFI16 binding to viral DNA initiates LLPS and induction of cytokines during herpes simplex virus type 1 (HSV-1) infection. Multiple phosphorylation sites within an intrinsically disordered region (IDR) function combinatorially to activate IFI16 LLPS, facilitating filamentation. Regulated by CDK2 and GSK3β, IDR phosphorylation provides a toggle between active and inactive IFI16 and the decoupling of IFI16-mediated cytokine expression from repression of viral transcription. These findings show how IFI16 switch-like phase transitions are achieved with temporal resolution for immune signaling and, more broadly, the multi-layered regulation of nuclear DNA sensors.
Topics: Cytokines; Herpesvirus 1, Human; Immunity, Innate; Interferons; Phosphorylation; Herpes Simplex; Embryo, Mammalian; Urochordata; Gene Expression Regulation, Viral; Cyclin-Dependent Kinase 2; Glycogen Synthase Kinase 3 beta; Humans; Animals
PubMed: 37283074
DOI: 10.1093/nar/gkad449 -
Human Vaccines & Immunotherapeutics Dec 2023The recombinant zoster vaccine (RZV) was licensed in the US for prevention of herpes zoster (HZ) in 2017. We conducted a literature search (January 1, 2017-August 1,... (Review)
Review
The recombinant zoster vaccine (RZV) was licensed in the US for prevention of herpes zoster (HZ) in 2017. We conducted a literature search (January 1, 2017-August 1, 2023) using PubMed, Embase, and Scopus to consolidate the real-world evidence related to RZV. Overall, RZV effectiveness against HZ was high across the studied populations in real-world settings, including adults aged ≥ 50 years and patients aged ≥ 18 years with immunodeficiency or immunosuppression. Effectiveness was higher with two doses versus one dose, especially in elderly people and immunocompromised individuals. The safety profile of RZV was broadly consistent with that established in clinical trials. RZV does not appear to increase the risk of disease flares in patients with immune-mediated diseases. Approximately two-thirds of individuals received a second RZV dose within 2-6 months after the first dose. Collectively, RZV effectiveness against HZ was high, and these real-world studies reaffirm its favorable benefit-risk profile.
Topics: Aged; Humans; Herpes Zoster; Herpes Zoster Vaccine; Herpesvirus 3, Human; Immunocompromised Host; Vaccines, Synthetic; Adolescent; Adult; Middle Aged
PubMed: 37967254
DOI: 10.1080/21645515.2023.2263979 -
Graefe's Archive For Clinical and... Aug 2023While typically affecting older adults and immunocompromised individuals, herpes zoster ophthalmicus (HZO) has been reported with varying manifestations and... (Review)
Review
PURPOSE
While typically affecting older adults and immunocompromised individuals, herpes zoster ophthalmicus (HZO) has been reported with varying manifestations and complications in children. In this review, we evaluate reported cases of pediatric HZO in the literature and discuss the epidemiology, risk factors, clinical presentation, treatment and outcomes.
METHODS
A literature search on PubMed, Scopus, and Web of Science databases was performed using the terms "pediatric herpes zoster ophthalmicus" and "herpes zoster ophthalmicus children." Publications that were not specific to HZO or pediatric populations were excluded, as were publications that were not available to review or not published in the English language.
RESULTS
Fifty-seven reports describing 130 cases of HZO or HZO-related complications were reviewed. Major risk factors for pediatric HZO included intrauterine exposure to varicella or primary varicella infection at a young age; HZO also occurred in patients who had received varicella vaccination. Both healthy and immunocompromised children were affected, with the majority of affected children being immunocompetent. The diagnosis of HZO is primarily clinical. Children appear to have good vision recovery and resolution of symptoms if they are treated promptly and if they adhere to treatment regimens, except for irreversible vision loss related to uncommon complications such as optic neuritis.
CONCLUSION
HZO occurs in both healthy and immunocompromised children. Recognizing this treatable condition is essential for reducing ocular and systemic morbidity. Long-term follow-up and assessments of the impact on health in adulthood are lacking. More systematic study is needed to determine the incidence of HZO in children and appropriate diagnostic and treatment protocols for the care of pediatric patients with HZO.
Topics: Humans; Child; Aged; Herpes Zoster Ophthalmicus; Chickenpox; Herpesvirus 3, Human; Incidence; Morbidity
PubMed: 36949170
DOI: 10.1007/s00417-023-06033-0 -
International Journal of Molecular... Nov 2023Kaempferol and its derivatives are flavonoids found in various plants, and a considerable number of these have been used in various medical applications worldwide.... (Review)
Review
Kaempferol and its derivatives are flavonoids found in various plants, and a considerable number of these have been used in various medical applications worldwide. Kaempferol and its compounds have well-known antioxidant, anti-inflammatory and antimicrobial properties among other health benefits. However, the antiviral properties of kaempferol are notable, and there is a significant number of experimental studies on this topic. Kaempferol compounds were effective against DNA viruses such as hepatitis B virus, viruses of the alphaherpesvirinae family, African swine fever virus, and pseudorabies virus; they were also effective against RNA viruses, namely feline SARS coronavirus, dengue fever virus, Japanese encephalitis virus, influenza virus, enterovirus 71, poliovirus, respiratory syncytial virus, human immunodeficiency virus, calicivirus, and chikungunya virus. On the other hand, no effectiveness against murine norovirus and hepatitis A virus could be determined. The antiviral action mechanisms of kaempferol compounds are various, such as the inhibition of viral polymerases and of viral attachment and entry into host cells. Future research should be focused on further elucidating the antiviral properties of kaempferol compounds from different plants and assessing their potential use to complement the action of antiviral drugs.
Topics: Swine; Animals; Cats; Humans; Mice; Kaempferols; African Swine Fever Virus; RNA Viruses; Enterovirus; Antiviral Agents
PubMed: 38003488
DOI: 10.3390/ijms242216299 -
Frontiers in Immunology 2023Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of...
INTRODUCTION
Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR.
METHODS
All participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex.
RESULTS
We included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score <5 (28% of the cohort), 5-10 (45% of the cohort), and >10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001).
CONCLUSION
In conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk.
Topics: Humans; Infant; Prospective Studies; Interleukin-12 Subunit p40; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Herpesviridae Infections; Organ Transplantation; Cytomegalovirus; Herpesvirus 3, Human; Herpesvirus 2, Human; Cytomegalovirus Infections; Immunity; Poly I
PubMed: 37465673
DOI: 10.3389/fimmu.2023.1183703 -
Nature Communications Jan 2024Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are...
Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.
Topics: Female; Mice; Animals; Oncolytic Virotherapy; Drug Resistance, Neoplasm; Nuclear Proteins; Transcription Factors; Glioma; Simplexvirus; Oncolytic Viruses
PubMed: 38167409
DOI: 10.1038/s41467-023-44576-2