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Journal of Virology Jul 2023Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination...
Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination has been used to prevent PRV infection, the virus cannot be eliminated in pigs. Thus, novel antiviral agents as complementary to vaccination are urgently needed. Cathelicidins (CATHs) are host defense peptides that play an important role in the host immune response against microbial infections. In the study, we found that the chemical synthesized chicken cathelicidin B1 (CATH-B1) could inhibit PRV regardless of whether CATH-B1 was added pre-, co-, or post-PRV infection and . Furthermore, coincubation of CATH-B1 with PRV directly inactivated virus infection by disrupting the virion structure of PRV and mainly inhibited virus binding and entry. Importantly, pretreatment of CATH-B1 markedly strengthened the host antiviral immunity, as indicated by the increased expression of basal interferon-β (IFN-β) and several IFN-stimulated genes (ISGs). Subsequently, we investigated the signaling pathway responsible for CATH-B1-induced IFN-β production. Our results showed that CATH-B1 induced phosphorylation of interferon regulatory transcription factor 3 (IRF3) and further led to production of IFN-β and reduction of PRV infection. Mechanistic studies revealed that the activation of Toll-like receptor 4 (TLR4), endosome acidification, and the following c-Jun N-terminal kinase (JNK) was responsible for CATH-B1-induced IRF3/IFN-β pathway activation. Collectively, CATH-B1 could markedly inhibit PRV infection via inhibiting virus binding and entry, direct inactivation, and regulating host antiviral response, which provided an important theoretical basis for the development of antimicrobial peptide drugs against PRV infection. Although the antiviral activity of cathelicidins could be explained by direct interfering with the viral infection and regulating host antiviral response, the specific mechanism of cathelicidins regulating host antiviral response and interfering with pseudorabies virus (PRV) infection remains elusive. In this study, we investigated the multiple roles of cathelicidin CATH-B1 against PRV infection. Our study showed that CATH-B1 could suppress the binding and entry stages of PRV infection and direct disrupt PRV virions. Remarkably, CATH-B1 significantly increased basal interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression levels. Furthermore, TLR4/c-Jun N-terminal kinase (JNK) signaling was activated and involved in IRF3/IFN-β activation in response to CATH-B1. In conclusion, we elucidate the mechanisms by which the cathelicidin peptide direct inactivates PRV infection and regulates host antiviral IFN-β signaling.
Topics: Swine; Animals; Herpesvirus 1, Suid; Cathelicidins; Toll-Like Receptor 4; Interferon-beta; Antiviral Agents; Pseudorabies
PubMed: 37314341
DOI: 10.1128/jvi.00706-23 -
Advanced Materials (Deerfield Beach,... Aug 2023Development of biologically relevant and clinically relevant human cerebral cortex models is demanded by mechanistic studies of human cerebral cortex-associated...
Development of biologically relevant and clinically relevant human cerebral cortex models is demanded by mechanistic studies of human cerebral cortex-associated neurological diseases and discovery of preclinical neurological drug candidates. Here, rational design of human-sourced brain-like cortical tissue models is demonstrated by reverse engineering and bionic design. To implement this design, the acoustic assembly technique is employed to assemble hiPSC-derived neural progenitors and neurons separately in a label-free and contact-free manner followed by subsequent neural differentiation and culture. The generated microtissues encapsulate the neuronal microanatomy of human cerebral-cortex tissue that contains six-layered neuronal architecture, a 400-µm interlayer distance, synaptic connections between interlayers, and neuroelectrophysiological transmission. Furthermore, these microtissues are infected with herpes simplex virus type I (HSV-1) virus, and the HSV-induced pathogenesis associated with Alzheimer's disease is determined, including neuron loss and the expression of Aβ. Overall, a high-fidelity human-relevant in vitro histotypic model is provided for the cerebral cortex, which will facilitate wide applications in probing the mechanisms of neurodegenerative diseases and screening the candidates for neuroprotective agents.
Topics: Humans; Induced Pluripotent Stem Cells; Neurons; Alzheimer Disease; Herpesvirus 1, Human; Acoustics; Cerebral Cortex
PubMed: 37170683
DOI: 10.1002/adma.202210631 -
The Medical Clinics of North America Mar 2024Genital herpes is a chronic, lifelong sexually transmitted viral infection, which can cause recurrent, self-limited genital ulcers. It is caused by herpes simplex virus... (Review)
Review
Genital herpes is a chronic, lifelong sexually transmitted viral infection, which can cause recurrent, self-limited genital ulcers. It is caused by herpes simplex virus (HSV) type 1 and type 2 viruses. Genital HSV infection is a very prevalent STI, which causes self-limited, recurrent genital ulcers. Treatment decreases duration of symptoms and signs and can be provided as episodic or suppressive therapy. Genital herpes can have a substantial impact during pregnancy and on sexual health in general. Counseling on natural history, transmission, treatment, and management of sexual partners is an integral part of management of genital herpes.
Topics: Female; Pregnancy; Humans; Herpes Genitalis; Simplexvirus; Ulcer; Counseling; Primary Health Care
PubMed: 38331482
DOI: 10.1016/j.mcna.2023.08.016 -
Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1.Acta Pharmacologica Sinica Sep 2023Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis...
Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis mechanisms. In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid (RA) in vivo and in vitro. Mice were administered RA (11.7, 23.4 mg·kg·d, i.g.) or acyclovir (ACV, 206 mg·kg·d, i.g.) for 23 days. The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7. At the end of RA or ACV treatment, mouse plasma samples and brain tissues were collected for analysis. We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice. In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone (CORT) plus HSV-1, RA (100 μM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of viral proteins and genes. We demonstrated that CORT (50 μM) triggered lipoxygenase 15 (ALOX15)-mediated redox imbalance in the neuronal cells, increasing the level of 4-HNE-conjugated STING, which impaired STING translocation from the endoplasmic reticulum to Golgi; the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility. We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15, thus RA could rescue stress-weakened neuronal innate immune response, thereby reducing HSV-1 susceptibility in vivo and in vitro. This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.
Topics: Humans; Animals; Mice; Herpesvirus 1, Human; Lipid Peroxidation; Neuroblastoma; Acyclovir; Herpes Simplex
PubMed: 37193755
DOI: 10.1038/s41401-023-01095-6 -
The Lancet. Rheumatology Apr 2024The 2019 European Alliance of Associations for Rheumatology (EULAR) recommendations on herpes zoster vaccination for adult patients with rheumatic immune-mediated... (Review)
Review
The 2019 European Alliance of Associations for Rheumatology (EULAR) recommendations on herpes zoster vaccination for adult patients with rheumatic immune-mediated inflammatory diseases stated that these patients are at increased risk of herpes zoster compared with the general population. However, these recommendations lack clarity and specificity and are cautiously phrased, which might cause physicians to underestimate the importance of herpes zoster vaccination for these patients, potentially resulting in suboptimal protection. Since the formulation of the 2019 EULAR guidelines, new data on herpes zoster in patients with immune-mediated inflammatory diseases have been published. Moreover, a recombinant herpes zoster vaccine (Shingrix) has become available that can be given to these patients in a more accessible manner than the original live-attenuated vaccine (Zostavax). Here, we evaluate existing evidence on risk factors for herpes zoster and the safety and efficacy of the recombinant vaccine in patients with rheumatic immune-mediated inflammatory diseases and discuss the necessity of herpes zoster vaccination for these patients.
Topics: Humans; Herpes Zoster Vaccine; Herpes Zoster; Herpesvirus 3, Human; Vaccination; Vaccines, Attenuated; Rheumatic Diseases
PubMed: 38373432
DOI: 10.1016/S2665-9913(24)00019-5 -
European Journal of Neurology Sep 2023Epstein-Barr virus (EBV) is implicated in multiple sclerosis (MS) risk; evidence for other herpesviruses is inconsistent. Here, we test blood markers of infection with...
BACKGROUND AND PURPOSE
Epstein-Barr virus (EBV) is implicated in multiple sclerosis (MS) risk; evidence for other herpesviruses is inconsistent. Here, we test blood markers of infection with human herpesvirus 6 (HHV-6), varicella zoster virus (VZV), and cytomegalovirus (CMV) as risk factors for a first clinical diagnosis of central nervous system demyelination (FCD) in the context of markers of EBV infection.
METHODS
In the Ausimmune case-control study, cases had an FCD, and population controls were matched on age, sex, and study region. We quantified HHV-6- and VZV-DNA load in whole blood and HHV-6, VZV, and CMV antibodies in serum. Conditional logistic regression tested associations with FCD risk, adjusting for Epstein-Barr nuclear antigen (EBNA) IgG, EBV-DNA load, and other covariates.
RESULTS
In 204 FCD cases and 215 matched controls, only HHV-6-DNA load (positive vs. negative) was associated with FCD risk (adjusted odds ratio = 2.20, 95% confidence interval = 1.08-4.46, p = 0.03). Only EBNA IgG and HHV-6-DNA positivity were retained in a predictive model of FCD risk; the combination had a stronger association than either alone. CMV-specific IgG concentration modified the association between an MS risk-related human leucocyte antigen gene and FCD risk. Six cases and one control had very high HHV-6-DNA load (>1.0 × 10 copies/mL).
CONCLUSIONS
HHV-6-DNA positivity and high load (possibly due to inherited HHV-6 chromosomal integration) were associated with increased FCD risk, particularly in association with markers of EBV infection. With growing interest in prevention/management of MS through EBV-related pathways, there should be additional consideration of the role of HHV-6 infection.
Topics: Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Case-Control Studies; Herpesvirus 6, Human; Multiple Sclerosis; Herpesvirus 3, Human; Cytomegalovirus Infections; Immunoglobulin G; Central Nervous System
PubMed: 37306550
DOI: 10.1111/ene.15919 -
The Clinical Journal of Pain Aug 2023Herpes zoster (HZ) is a painful condition caused by the reactivation of the varicella-zoster virus, negatively affecting the lives of patients. In this post hoc... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Herpes zoster (HZ) is a painful condition caused by the reactivation of the varicella-zoster virus, negatively affecting the lives of patients. In this post hoc analysis, we describe the impact of HZ pain on the health-related quality of life (HRQoL) and activities of daily living (ADL) of immunocompetent individuals 50 years of age and older and in hematopoietic stem cell transplantation (HSCT) recipients age 18 years of age and older.
MATERIALS AND METHODS
ZOE-50 (NCT01165177), ZOE-70 (NCT01165229), and ZOE-HSCT (NCT01610414) were phase III, randomized studies conducted in immunocompetent adults 50 years of age and older and 70 years of age and older and in HSCT recipients age 18 years of age and older, respectively. This analysis was performed on patients who experienced an HZ episode in the placebo groups. The impact of varying levels of HZ pain on HRQoL and ADL was analyzed using data from the Zoster Brief Pain Inventory (ZBPI) and the Short Form Health Survey 36 (SF-36) and EQ-5D questionnaires.
RESULTS
A total of 520 immunocompetent and 172 HSCT individuals with HZ were included. SF-36 and EQ-5D domain scores showed a significant relationship between increased HZ pain and worsening HRQoL. For every increase of 1 in the ZBPI pain score, the estimated mean decrease (worsening) in score in the ZOE-50/70 and ZOE-HSCT, respectively, was 2.0 and 2.4 for SF-36 Role Physical; 2.1 and 1.8 for SF-36 Social Functioning; and 0.041 and 0.045 for EQ-5D utility. Sleep and General activities were the ADL components most affected.
DISCUSSION
Moderate and severe HZ pain had a substantial negative impact on all aspects of HRQoL and ADL. This impact was independent of age and immunosuppression.
Topics: Adult; Humans; Adolescent; Herpesvirus 3, Human; Activities of Daily Living; Quality of Life; Herpes Zoster; Pain
PubMed: 37166199
DOI: 10.1097/AJP.0000000000001129 -
Cellular Oncology (Dordrecht) Dec 2023High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary,...
PURPOSE
High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.
METHODS
iNSCs cells expressing HSV-TK (iNSCs) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCs and the combinational therapeutics of iNSCs and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.
RESULTS
PBMC-derived iNSCs possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCs/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCs/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.
CONCLUSIONS
PBMC-derived iNSCs showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCs therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.
Topics: Humans; Animals; Mice; Glioblastoma; Simplexvirus; Leukocytes, Mononuclear; Ganciclovir; Thymidine Kinase
PubMed: 37420122
DOI: 10.1007/s13402-023-00842-5 -
Viruses Jul 2023Herpes simplex virus type 1 (HSV-1) infections are prevalent illnesses that can cause mucocutaneous ulcerative disease, keratitis, and genital herpes. In patients with...
Herpes simplex virus type 1 (HSV-1) infections are prevalent illnesses that can cause mucocutaneous ulcerative disease, keratitis, and genital herpes. In patients with compromised immune systems, the infection can lead to serious problems, such as encephalitis. Additionally, neonatal infections can cause brain problems and even death. Current first-line antiviral drugs are nucleoside analog inhibitors that target viral polymerase, and resistant strains have emerged. As a result, new drugs with distinct action modes are needed. Recent research indicates that cyclin-dependent kinases (CDKs) are prospective antiviral targets. Thus, CDK inhibitors may be effective antiviral agents against HSV-1 infection. In this study, we examined a panel of CDK inhibitors that target CDKs in the present study. BMS-265246 (BMS), a CDK 1/2 inhibitor, was found to effectively limit HSV-1 multiplication in Vero, HepG2, and Hela cells. A mechanism of action study suggested that BMS inhibits the early stages of viral replication when added early in the viral infection. The suppression of multiple steps in viral replication by BMS was revealed when HSV-1 infected cells were treated at different time periods in the viral life cycle. Our results suggest that BMS is a potent anti-HSV-1 agent and unique in that it may interfere with multiple steps in HSV-1 replication.
Topics: Infant, Newborn; Humans; Herpesvirus 1, Human; HeLa Cells; Protein Kinase Inhibitors; Herpes Simplex; Antiviral Agents; Cyclin-Dependent Kinases
PubMed: 37631985
DOI: 10.3390/v15081642 -
Veterinary Microbiology Sep 2023Pseudorabies virus (PRV) mainly causes pseudorabies (PR) or Aujeszky's disease in pigs and can infect humans, raising public health concerns about zoonotic and...
Pseudorabies virus (PRV) mainly causes pseudorabies (PR) or Aujeszky's disease in pigs and can infect humans, raising public health concerns about zoonotic and interspecies transmission of PR. With the emergence of PRV variants in 2011, the classic attenuated PRV vaccine strains have failed to protect many swine herds against PR. Herein, we developed a self-assembled nanoparticle vaccine that induces potent protective immunity against PRV infection. PRV glycoprotein D (gD) was expressed using the baculovirus expression system and further presented on the lumazine synthase (LS) 60-meric protein scaffolds via the SpyTag003/SpyCatcher003 covalent coupling system. In mouse and piglet models, LSgD nanoparticles emulsified with the ISA 201VG adjuvant elicited robust humoral and cellular immune responses. Furthermore, LSgD nanoparticles provided effective protection against PRV infection and eliminated pathological symptoms in the brain and lungs. Collectively, the gD-based nanoparticle vaccine design appears to be a promising candidate for potent protection against PRV infection.
Topics: Humans; Animals; Swine; Mice; Herpesvirus 1, Suid; Pseudorabies; Adjuvants, Immunologic; Vaccines, Attenuated; Swine Diseases; Pseudorabies Vaccines
PubMed: 37327558
DOI: 10.1016/j.vetmic.2023.109799