Glycoprotein B (gB) serves as the viral fusion protein for herpes simplex virus (HSV), mediating fusion between viral and host membranes resulting in infection. As such, gB represents a critical target for the host immune system with high potential relevance for vaccine design. Here, we investigated the mechanisms of protection for a panel of gB-specific monoclonal antibodies (mAbs) in a mouse model of neonatal HSV (nHSV) infection. Depending on dose, viral neutralization contributed, but Fc effector functions were critical for mAb-mediated protection against nHSV mortality. Moreover, adeno-associated virus-mediated in vivo expression of a gB-specific mAb in mice provided transgenerational protection against HSV-1 and HSV-2 mortality. These findings demonstrate that antibodies targeting gB can serve as potent therapeutics and that they require diverse functional profiles to afford optimal protection, informing vaccine design.IMPORTANCEAntibodies represent promising drugs for the prevention and treatment of viral infections, especially when efficacious vaccines are unavailable. Determining the dominant mechanisms of Ab-mediated protection is a critical step in the design and optimization of potential antibody therapies. In this study of antibody-mediated protection of neonatal mice from herpes simplex virus, efficacy and mechanism of action of antibodies that recognize viral glycoprotein B (gB) were dependent on dose, effector functions, and viral neutralization capacity. Overall, while viral neutralization likely contributes to monoclonal antibody-mediated protection, the ability for gB-specific antibodies to mediate Fc domain-dependent effector functions was unexpectedly crucial.

The mechanisms by which microglia respond to viral central nervous system (CNS) pathogens are now becoming apparent with the demonstration that they express an array of pattern recognition receptors that include cytosolic sensors for exogenous nucleic acids. We have previously shown that microglia express Z-DNA binding protein 1 (ZBP1) and found that this sensor contributes to their inflammatory responses to the clinically relevant DNA virus, herpes simplex virus-1 (HSV-1). More recently, we showed that ZBP1 serves as a restriction factor for HSV-1 in murine astrocytes and is associated with the induction of both necroptotic and apoptotic cell death pathways in these cells. Here, we demonstrate that this cytosolic DNA sensor similarly functions as a HSV-1 restriction factor in primary murine microglia. However, unlike astrocytes, we have determined that a neuroinvasive clinically-derived HSV-1 isolate induces necroptosis, but not apoptosis, in these myeloid cells in a ZBP1-dependent as well as a ZBP1-independent manner. Interestingly, we found that a laboratory adapted HSV-1 strain elicits microglial apoptosis in a ZBP-1-independent manner, in addition to both ZBP1-dependent and independent necroptosis, indicating that viral strain-specific differences may exist. However, it remains to be seen whether ZBP1-mediated cell death in microglia contributes significantly to host protection or, rather, exacerbates DNA virus-associated CNS pathology in mice.

Herpes simplex virus (HSV) infections impose a substantial global health burden, yet regional, subtype-specific epidemiology in dermatology settings remains underexplored. We analyzed laboratory-confirmed HSV tests (PCR, viral culture and IgG ELISA) performed at the Dermatology Hospital of Southern Medical University from 2019 to 2024 to characterize subtype distribution, demographics, anatomical sites, temporal trends and diagnostic performance. Overall, HSV was detected in 32.84% of patients, with HSV-2 significantly more prevalent than HSV-1 (22.83% vs 10.02%, p < 0.0001). Over time, HSV-1 increased (23.55% to 34.65%, p = 0.0060) while HSV-2 declined. HSV-1 was more common in females than males (14.26% vs 7.57%, p < 0.0001) and in children (highest in ages 0-9 years: 24.71%), whereas HSV-2 peaked in adults (ages 40-49 years: 29.3%). Anatomically, HSV-1 infections were predominantly oral/cephalic, while HSV-2 occurred mainly in anogenital sites (89.94%). Viral culture showed high specificity (99.83%) but lower sensitivity (64.52%) relative to PCR, supporting PCR as the preferred diagnostic method. Latent infections (47.44%) confirmed HSV's lifelong persistence. These findings indicate current dominance of HSV-2 alongside a rising burden of HSV-1, with distinct demographic and anatomical patterns, and underscore the need for multicenter data to refine regional epidemiology and inform targeted prevention strategies.

Direct comparison of three herpes simplex virus-2 vaccine candidates using peripheral or mucosal routes of vaccination.

Herpes simplex virus (HSV)-1 infection of cortical neurones is a leading cause of encephalitis. Whilst we have substantial knowledge about the molecular virology of HSV-1 lytic infection in cells of the periphery, like keratinocytes or fibroblasts, we know much less about infection of human neurones owing to the challenges of working with neuronal cell-based models. Here, we demonstrate the use of a human induced pluripotent stem cell-derived cortical neurone model (i3Neurones) for HSV-1 infection. i3Neurones are highly scalable and can be rapidly and efficiently differentiated into an isogenic population of cortical glutamatergic neurones. We show that i3Neurones support the full HSV-1 lytic replication cycle. We present an optimized protocol for the infection of i3Neurones with HSV-1 that allows their synchronous infection at near-100% efficiency and optimized fixation methods that preserve organelle and neurite structure for immunocytochemistry analysis. Our study highlights i3Neurones as a robust, scalable platform for microscopy and biochemical studies of HSV-1 and other neurotropic pathogens.

Our previous studies demonstrated that macrophages play a crucial role in both primary and latent herpes simplex virus 1 (HSV-1) infections. Here, we sought to determine whether HSV-1 exposure induces long-lasting functional and epigenetic changes in macrophages consistent with trained immunity, leading to enhanced responses upon secondary stimulation. To explore this, we performed Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) analysis on isolated spleen- and bone marrow (BM)-derived macrophages from latently infected mice before and after stimulation with UV-inactivated virus to identify open chromatin regions indicative of changes in gene regulation. Additionally, we performed flow cytometric analysis of infected spleen macrophages, BM-derived macrophages, corneas, and the trigeminal ganglia (TG). Moreover, to assess the durability of training response to infection, we evaluated responses after secondary infection. The study revealed that immunity-related GTPase family M protein (IRGM1) expression in isolated macrophages from latently infected mice was significantly elevated after stimulation, compared with that of more than 900 genes with open or closed chromatin accessibility. Flow cytometry further confirmed a higher proportion of IRGM1+ macrophages in the spleen, BM, cornea, and the TG of latently infected mice compared with mock-infected controls. The qRT-PCR determined that macrophages isolated from the spleen, trigeminal ganglia, and BM of latently infected mice continued to exhibit elevated IRGM1 expression levels relative to controls. Collectively, our findings indicate that macrophages develop a durable trained immunity to HSV-1 infection, with IRGM1 emerging as a key component in the long-term maintenance of macrophage immunological memory.

Abrocitinib, a selective Janus kinase (JAK)-1 inhibitor, is approved for the treatment of moderate-to-severe atopic dermatitis (AD). Although several real-world studies evaluated the safety and efficacy of abrocitinib, most have been limited by small sample sizes, and there are limited data on South Korean patients with AD. In addition, real-world comparative data across oral JAK inhibitors for AD remain limited. We conducted a retrospective, single-center cohort study at the National Medical Center in Seoul, Korea. Patients aged ≥ 12years with moderate-to-severe AD (baseline EASI ≥ 7) who initiated abrocitinib between September 2022 and April 2024 were included in the primary cohort; additional cohorts treated with upadacitinib or baricitinib during predefined periods were analyzed for between-drug comparisons. Efficacy was assessed at baseline, week2, and week16 using the Eczema Area and Severity Index (EASI) and patient-reported outcomes (PROs). Safety was evaluated by adverse events (AEs), physical examinations, and laboratory tests. Of the 66 patients enrolled, 57 patients completed 16weeks of abrocitinib treatment in the analysis. The mean EASI score significantly decreased after 16weeks. At week16, 94.4%, 72.2%, and 25.9% of patients with AD achieved EASI-50, -75, and -90, respectively. Additionally, of the 21 patients who had previously experienced biologics or other JAK inhibitors, 95.5%, 72.7%, and 22.7% achieved EASI-50, -75, and -90, respectively. Further analysis of the EASI breakdown showed improvements of more than 80% across all body regions, with the lower extremities showing the greatest reduction (87.5%) and lichenification exhibiting the highest symptom improvement (89.7%). In descriptive, unadjusted comparisons, abrocitinib showed numerically higher EASI-50 and EASI-75 response rates at week16 than upadacitinib and baricitinib. Acne was the most frequent adverse event with abrocitinib (43.9%), followed by urticaria (24.6%) and herpes simplex infection (12.3%); no dose reductions or treatment discontinuations due to adverse events occurred. Abrocitinib demonstrates real-world efficacy and safety in moderate-to-severe AD, including patients with inadequate responses to other dupilumab or JAK inhibitors, including those with prior exposure to biologics or other JAK inhibitors.

Numerous studies suggest that abnormal upregulation of the complement cascade, a key component of the innate immune system, is involved in the pathogenesis of Alzheimer's disease (AD), also contributing to synapse elimination in the brain. Several pieces of evidence suggest that recurrent herpes simplex virus-1 (HSV-1) infection reaching the brain is one of the AD risk factors, including those reporting synaptic loss and consequent cognitive deficit following multiple virus replication in the brain. However, the role of complement cascade activation in such events remains unexplored. Murine primary neurons co-cultured or not with microglial BV2 cells and organotypic hippocampal brain slices were used as experimental models of HSV-1 infection. Virus effects on complement cascade activation and synaptic loss were assessed by evaluation of protein and mRNA levels of specific complement components and synaptic markers. Confocal immunofluorescence microscopy was used to analyze microglial phagocytosis of synapses. To evaluate the role of complement cascade activation in such event, experimental models were treated with a neutralizing anti-C3 antibody within the infection. Two-photon imaging and patch-clamp recordings of organotypic hippocampal slices were used to quantify dendritic spine density on secondary apical dendrites of CA1 pyramidal neurons and synaptic transmission. We first found that HSV-1 infection significantly upregulates the expression of components of the classical complement cascade at both mRNA and protein levels, and promotes their localization at synapses. Then, we provide evidence that HSV-1 infection causes increased microglial phagocytosis of synapses, which is partially prevented when the complement cascade is inhibited. Furthermore, by exploiting murine organotypic hippocampal slices, we confirmed that the virus triggers synaptic damage through microglial pruning of synapses via a complement-dependent mechanism. Importantly, in infected CA1 neurons, we detected a significant decrease in spine density, which was paralleled by functional alterations in synaptic transmission. Both events were rescued when infection is performed in the presence of an antibody neutralizing the complement C3 protein. Our data indicate that HSV-1 infection triggers aberrant complement activation and complement-mediated microglial engulfment of damaged synapses, further supporting the role of HSV-1 in neurodegeneration.

Herpes simplex virus (HSV) is an endemic pathogen, infecting most adults world-wide. HSV infection can cause a wide spectrum of disease outcomes, ranging from asymptomatic infection or mild lesions to rare cases of infectious keratitis, encephalitis, and death. HSV genome sequences have been shown to differ between individual patients, as well as within individuals. To date, the vast majority of publicly available HSV genomic data has come from Europe and North America. Our current understanding of these patterns are missing data from under-sampled populations, particularly in South America, Africa, and Asia. Also missing have been HSV samples from non-industrial (e.g., agricultural, pastoral) populations, for which the natural environment plays a large role in health and disease dynamics. In this study, we capitalized on Whatman FTA card stabilization of DNA to develop a procedure for capturing oral and genital swabs from a geographically isolated pastoralist population in a desert region of northern Namibia. These are the first data to document HSV diversity in this type of remote setting. These are also the first HSV genomes from Namibia. These approaches may prove useful in broadening the accessibility of viral detection for these chronic pathogens, help improve diagnostics, and raise public health awareness about the burden of these pathogens in under-served populations.

Neonatal herpes simplex virus (HSV) infection, primarily caused by HSV-2, carries a significant risk of severe morbidity, including neurological impairment and developmental delays, without timely diagnosis and intervention. The early identification of atypical cutaneous manifestations at birth and the prompt empirical initiation of high-dose intravenous acyclovir in suspected cases are crucial to prevent systemic dissemination and improve outcomes. Nevertheless, due to the unique neonatal immune response and limitations of current therapies, significant long-term sequelae such as chorioretinitis and global developmental delay may still develop, particularly when recommended suppressive antiviral regimens are not followed. A late-preterm neonate (36+2 weeks) exhibited irregular white atrophic patches and scattered erosions on the trunk and neck at birth, which rapidly evolved into vesiculopustular lesions within hours. Cutaneous HSV-2 infection was confirmed by positive IgM serology and lesion PCR. Cerebrospinal fluid (CSF) analysis and HSV-2 PCR during the initial admission were negative. A history of paternal genital HSV late in gestation was reported. The infant received a 14-day course of high-dose intravenous acyclovir for presumed skin-eye-mouth disease, leading to cutaneous healing. Readmission occurred approximately three days post-discharge due to neurological decline. Blood culture identified Escherichia coli, while CSF showed marked hyperproteinorrachia with a CSF WBC count at the borderline/upper-limit range (20×10^6/L) rather than unequivocal pleocytosis, and an initially normal CSF glucose, without CSF microbiological confirmation of meningitis; therefore, bacterial meningitis could not be confirmed on readmission, although E. coli bacteremia with possible CNS involvement was considered and treated empirically. While repeat HSV-2 PCR from blood and CSF remained negative, high-dose acyclovir was empirically continued for 21 days, given the concern for potential CNS viral reactivation. HSV chorioretinitis was diagnosed during this admission, with subsequent funduscopy showing partial resolution of acute inflammation. By early childhood, cranial MRI revealed periventricular white-matter abnormalities, and the child manifested severe global developmental delay, later diagnosed as cerebral palsy, necessitating ongoing multidisciplinary rehabilitation. This case highlights that congenital HSV-2 infection can present with atypical cutaneous findings at delivery, mandating high clinical suspicion and immediate empirical antiviral therapy. An initially negative CSF HSV PCR and benign cytochemistry do not guarantee against subsequent ocular or neurological involvement. This report emphasizes the imperative for routine ophthalmologic screening, extended intravenous therapy when dissemination cannot be ruled out, consideration of oral suppression in high-risk infants, and long-term, multidisciplinary follow-up for all neonates diagnosed with HSV infection, irrespective of the initial disease classification.

The evaluation of neonatal herpes simplex virus (HSV) includes HSV culture and/or polymerase chain reaction (PCR) of different surfaces, cerebrospinal fluid (CSF), and blood. However, the impact of blood HSV PCR for the management of neonatal HSV infections has not been well-established. To evaluate the impact of blood HSV PCR results in the management (i.e., clinical decision-making regarding treatment) of neonatal HSV infections at our institution, where this test is performed at an outside facility. We retrospectively reviewed the medical records of all neonates tested for HSV DNA in blood from January 1, 2018, to July 31, 2023, at our children's hospital. A total of 149 medical records were analyzed, of which seven had positive blood HSV PCR. These seven patients and five of 142 patients with negative blood HSV PCR had a positive HSV PCR result from another site, and they were managed according to those results. The mean turnaround time (TAT) for the results of blood HSV PCRwas three and a half days for positive results and four days for negative results. In most patients with negative PCR from other sites, including CSF, acyclovir was discontinued before the blood HSV PCR results were back. Acyclovir was not discontinued until the results were available in only 12 of 134 neonates who had all negative results and available information about management.Statistical analysis showed that blood HSV PCR did not significantly impact the management of these neonates. Conclusions: Our study does not support the use of blood HSV PCR in the evaluation of neonatal HSV infection specifically in institutions where the test is not performed in-house, because the test results are not available in a timely fashion to have an impact on the management of these neonates.

TMEM41B contributes to atherosclerosis by promoting lipid synthesis in vascular smooth muscle cells via fatty acid synthase stabilization.

'Herpes simplex virus infection in a bipulmonary transplant recipient'.

Alzheimer's disease (AD) and dementia create major global health and economic burdens. Herpes simplex virus (HSV) infects over 3 billion people, and chronic infection is increasingly linked to neurodegeneration. To evaluate whether antiviral therapy for oral, mucocutaneous, or anogenital HSV lowers the subsequent risk of AD and dementia. A retrospective cohort study with propensity-score matching was performed in the TriNetX Research Network. On 24 May 2024, 615,324 individuals with HSV were identified; those with prior AD, intracranial injury, or cerebral infarction were excluded. Matching balanced age, sex, race, body-mass index, smoking, diabetes, and hypertension between antiviral-treated and untreated groups. Therapies included acyclovir, valacyclovir, penciclovir, ganciclovir, valganciclovir, and famciclovir. Incidences of AD and dementia were identified by ICD-10 codes, and relative risks (RR) with 95% confidence intervals (CI) were calculated. After matching, 231,277 patients per cohort (mean age 36.8 y; 67.7% female) were analyzed. Antiviral treatment for oral/mucocutaneous HSV significantly reduced the risk of AD (RR 0.87; 95% CI 0.73-0.92) and dementia (RR 0.83; 95% CI 0.77-0.90). No significant association was observed for anogenital HSV. Antiviral therapy for oral or mucocutaneous HSV was associated with a 13% to 17% reduction in risk for AD and dementia. These findings suggest that early antiviral management of HSV infections may represent a feasible preventive strategy against neurodegenerative disease, meriting prospective confirmation. &nbsp.

Herpes Simplex Virus Pneumonia in Immunocompetent Patients Undergoing Cardiac Surgery: Case Series.

A UPLC-MS/MS assay for the quantification of the novel viral helicase-primase drug candidate adibelivir (IM-250) in human specimen.

Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious corneal blindness worldwide. Viral persistence and disease severity are strongly influenced by the virus's ability to modulate host immune responses; however, the mechanisms by which HSV-1 alters corneal immunity are incompletely understood. In particular, the role of virus-encoded microRNAs (v-miRs) in shaping corneal immune responses during herpes simplex infection remains unclear. We previosuly showed that inhibition of selected HSV-1 v-miRs reduced viral replication and disease severity in a mouse model of ocular infection. Building on these findings, the present study investigated how v-miR inhibition affects corneal immune responses. Using corneal tissue RNA from HSV-1-infected mice, we performed an immune profiling PCR array by analyzing the expression of 88 genes associated with immune cell markers and polarization states. Topical inhibition of miR-H1-5p, miR-H3-3p, and miR-H6-3p resulted in distinct patterns of immune gene expression compared with the control treatment. Inhibition of these v-miRs altered 16, 31, and 57 immune-related genes, respectively, spanning both myeloid- and lymphoid-associated pathways. Notably, the anti-inflammatory genes Arg1 and Il10 were consistently upregulated across all v-miR inhibitor-treated groups. In parallel, increased expression of the pro-resolution enzymes 15-lox and Alox5 suggested enhanced engagement of resolution pathways. Mechanistic studies demonstrated that v-miRs directly target immune regulatory genes through binding sites within their untranslated regions. Together, these findings suggest that HSV-1 v-miRs contribute to corneal immunopathology by suppressing anti-inflammatory and pro-resolving immune pathways, and that targeted inhibition of v-miRs may promote immune resolution during HSV-1-induced keratitis.

Inborn errors of immunity can underlie susceptibility to severe viral infection in humans. and the majority relate to defective induction of or response to antiviral type I interferon (IFN). However there is increasing awareness of defects in other cellular processes, that can predispose to severe infectious disease. Recently, defects in autophagy-related genes or -processes have been demonstrated to predispose to life-threatening viral diseases, including defects in autophagy-related genes in patients with herpes simplex virus and varicella zoster virus infections in the central nervous system, as well as impairment of noncanonical antiviral immunity in critical COVID-19. However, the molecular mechanisms and complex intersections between autophagy, metabolism, cell death, and inflammation, and how defects in autophagy-related proteins may interfere with these cellular processes, are only now starting to emerge. This review presents the current knowledge on inborn errors of autophagy discovered in patients with severe viral infection and discusses some of the remaining knowledge gaps in our understanding of how autophagy processes act against viruses, how immunopathology and lack of viral control ensues when they fail, and how these insights may be translated into clinical medicine.

Since 1993, the Australian Paediatric Surveillance Unit (APSU) has been conducting prospective national surveillance of rare conditions in Australian children, including communicable diseases and complications of communicable diseases. In 2024, fifteen communicable diseases and complications were under APSU surveillance: acute flaccid paralysis (AFP); congenital cytomegalovirus (cCMV) infection; dengue; severe acute hepatitis; neonatal/infant herpes simplex virus (HSV) infection; perinatal exposure to human immunodeficiency virus (HIV); paediatric HIV infection, juvenile-onset recurrent respiratory papillomatosis (JoRRP); severe complications of influenza (Flu); Japanese encephalitis virus infection; paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS); Q fever; congenital rubella infection/syndrome; congenital varicella syndrome; and neonatal varicella infection. A total of 1,350 paediatricians and other child health specialists received the monthly APSU report card (97% electronically) in 2024. A total of 237 notifications were received, with 174 confirmed as incident cases after excluding duplicates, errors and prevalent (historic) cases not previously reported. The incident cases included: Flu (n = 34) - one child died and only two children had received influenza vaccination; JoRRP (n = 1); NVI (n = 1); cCMV (n = 26); HSV (n = 8) - neurological sequelae were common; perinatal exposure to HIV (n = 15) - no cases of mother-to-child transmission identified; and rare emerging diseases dengue (n = 4) and PIMS-TS (n = 2). The non-polio AFP rate of ≥1case per 100,000 children aged < 15 years was again achieved. The APSU continues to be an important mechanism for obtaining enriched data on rare communicable diseases and their complications in Australian children, to better understand disease burden, and the effects of health interventions, over time.

Biliary atresia (BA) is one of the most destructive liver and biliary diseases in neonates and is characterized by progressive fibrous inflammatory obstruction of the intrahepatic and extrahepatic bile ducts, ultimately leading to liver fibrosis and liver failure. This study aimed to use integrated bioinformatics methods to identify differentially expressed genes (DEGs) in BA liver tissue, identify key genes, and explore their mechanisms in liver fibrosis. We obtained data from the gene expression omnibus (GEO) dataset GSE122340 [171 BA patients and 7 normal controls (NCs)]. DEGs were screened via the limma package, followed by gene ontology (GO)/kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network was constructed via STRING and Cytoscape, and core genes were selected via the maximum clique centrality (MCC), maximum neighborhood component (MNC), and degree algorithms from the CytoHubba plugin. Further focus was placed on the key gene EGF-like repeats and discoidin I-like domains 3 (EDIL3) through gene set enrichment analysis (GSEA), expression validation, subcellular localization analysis, and clinical tissue sample validation. To minimize batch effects, we performed ComBat correction on the combined gene expression data of GSE122340 and the validation dataset GSE46960 before interdataset comparison. We identified a total of 3706 DEGs, including 2774 upregulated DEGs and 932 downregulated DEGs. The functional enrichment analysis revealed that the DEGs were involved mainly in biological processes such as the cell cycle, DNA replication, and extracellular matrix organization, as well as signaling pathways such as herpes simplex virus infection, phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT), and tumor necrosis factor (TNF). Protein-protein interaction (PPI) network analysis revealed 7 core genes (BRCA1, TOP2A, BRCA2, BUB1B, HSP90AA1, PLK4, and EDIL3), with EDIL3 showing the greatest increase in BA. EDIL3 is located on chromosome 5, and its encoded protein is expressed primarily in the cell membrane and extracellular region. GSEA indicated that high EDIL3 expression was significantly associated with apoptosis and activation of the PI3K-AKT signaling pathway. Clinical sample validation revealed that EDIL3 expression was significantly elevated in BA liver tissue, and its high expression was significantly negatively correlated with the survival rate of patients' native livers. Discoidin I-like domain 3 is a novel gene with a potentially key role in BA-related liver fibrosis, possibly influencing the proliferation and apoptosis of cholangiocytes by regulating the PI3K-AKT signaling pathway, thereby participating in the occurrence and development of liver fibrosis. This study provides new insights into the molecular mechanisms and potential treatment strategies for BA.