-
Journal of Virology May 2022Herpesviruses assemble new viral particles in the nucleus. These nucleocapsids bud through the inner nuclear membrane to produce enveloped viral particles in the...
Herpesviruses assemble new viral particles in the nucleus. These nucleocapsids bud through the inner nuclear membrane to produce enveloped viral particles in the perinuclear space before fusing with the outer nuclear membrane to reach the cytoplasm. This unusual route is necessary since viral capsids are too large to pass through nuclear pores. However, the transient perinuclear nucleocapsids (250 nm in diameter) are also larger than the width of the perinuclear space (30 to 50 nm). Interestingly, linker of the nucleoskeleton and cytoskeleton (LINC) components SUN and KASH connect the inner and outer nuclear membranes and regulate their spacing. Previous work by others on the related pseudorabies virus and human cytomegalovirus showed that they functionally interact with SUN proteins. To clarify the role of SUN proteins, we explored their impact on herpes simplex virus 1 (HSV-1), another herpesvirus. Using dominant negative SUN mutants and RNA interference, we show that HSV-1 propagation is dependent on the LINC complex. In contrast to pseudorabies virus, SUN2 disruption by either approach led to increased HSV-1 extracellular viral yields. This SUN2 dependency may be linked to its greater impact on perinuclear spacing in infected cells compared to SUN1. Finally, the virus itself seems to modulate perinuclear spacing. The large size of herpesviruses prevents them from travelling across the nuclear pores, and they instead egress across the two nuclear membranes, generating short-lived enveloped perinuclear virions. This poses a challenge as the perinuclear space is smaller than the virions. This implies the separation (unzipping) of the two nuclear membranes to accommodate the viral particles. The LINC complex bridges the two nuclear membranes and is an important regulator of perinuclear spacing. Work by others hint at its functional implication during pseudorabies virus and cytomegalovirus propagation. The present study probes the importance for HSV-1 of the SUN proteins, the LINC components found in the inner nuclear membrane. Using dominant negative constructs and RNA interference (RNAi), the data reveal that SUN2 exhibits antiviral propriety toward HSV-1, as disrupting the protein leads to increased viral yields. This is in contrast with that reported for pseudorabies and suggests that differences among herpesviruses may, once again, prevail.
Topics: Animals; Cell Nucleus; Herpesvirus 1, Human; Herpesvirus 1, Suid; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Nuclear Envelope; Nucleocapsid; Virion
PubMed: 35435724
DOI: 10.1128/jvi.00453-22 -
Mayo Clinic Proceedings May 2019
Topics: Exanthema; Herpes Zoster; Herpesvirus 3, Human; Humans
PubMed: 31054599
DOI: 10.1016/j.mayocp.2019.03.020 -
Viruses May 2019Varicella-zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce... (Review)
Review
Varicella-zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian varicella virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.
Topics: Animals; Chickenpox; Disease Models, Animal; Ganglia; Guinea Pigs; Herpes Zoster; Herpesviridae Infections; Herpesvirus 3, Human; Macaca mulatta; Sigmodontinae; Viral Load; Viral Tropism; Virus Replication
PubMed: 31159224
DOI: 10.3390/v11060502 -
Frontiers in Immunology 2019Alphaherpesviruses are a large family of highly successful human and animal DNA viruses that can establish lifelong latent infection in neurons. All alphaherpesviruses... (Review)
Review
Alphaherpesviruses are a large family of highly successful human and animal DNA viruses that can establish lifelong latent infection in neurons. All alphaherpesviruses have a protein-rich layer called the tegument that, connects the DNA-containing capsid to the envelope. Tegument proteins have a variety of functions, playing roles in viral entry, secondary envelopment, viral capsid nuclear transportation during infection, and immune evasion. Recently, many studies have made substantial breakthroughs in characterizing the innate immune evasion of tegument proteins. A wide range of antiviral tegument protein factors that control incoming infectious pathogens are induced by the type I interferon (IFN) signaling pathway and other innate immune responses. In this review, we discuss the immune evasion of tegument proteins with a focus on herpes simplex virus type I.
Topics: Alphaherpesvirinae; Animals; Herpesvirus 1, Human; Humans; Immune Evasion; Immunity, Innate; Signal Transduction; Viral Structural Proteins; Virus Internalization; Virus Replication
PubMed: 31572398
DOI: 10.3389/fimmu.2019.02196 -
Experimental Neurology May 2022It has become widely appreciated that the spinal cord has significant neuroplastic potential, is not hard-wired, and that with traumatic injury and anatomical... (Review)
Review
It has become widely appreciated that the spinal cord has significant neuroplastic potential, is not hard-wired, and that with traumatic injury and anatomical plasticity, the networks that we once understood now comprise a new anatomy. Harnessing advances in neuroanatomical tracing to map the neuronal networks of the intact and injured spinal cord has been crucial to elucidating this new spinal cord anatomy. Many new techniques have been developed to identify these networks using a variety of retrograde and anterograde tracers. One method of tracing that has become more widely used to map anatomical changes is transneuronal tracing. Viral tracers are being increasingly used to map spinal networks, leading to an advanced understanding of spinal circuitry and host-donor-host interactions between the injured spinal cord and neural transplants. This review will highlight advances in neuronal tracing, specifically using pseudorabies virus (PRV), and its use in the intact, injured, and transplanted spinal cord.
Topics: Animals; Herpesvirus 1, Suid; Neuronal Plasticity; Neurons; Spinal Cord; Spinal Cord Injuries
PubMed: 35085573
DOI: 10.1016/j.expneurol.2022.113990 -
International Journal of Molecular... Jul 2023The proper functioning of mesenchymal stem cells (MSCs) is of paramount importance for the homeostasis of the body. Inflammation and infection can alter the function of...
The proper functioning of mesenchymal stem cells (MSCs) is of paramount importance for the homeostasis of the body. Inflammation and infection can alter the function of MSCs, which can also affect the regenerative potential and immunological status of tissues. It is not known whether human herpes simplex viruses 1 and 2 (HSV1 and HSV2), well-known human pathogens that can cause lifelong infections, can induce changes in MSCs. In non-healing ulcers, HSV infection is known to affect deeper tissue layers. In addition, HSV infection can recur after initially successful cell therapies. Our aim was to study the response of adipose-derived MSCs (ADMSCs) to HSV infection in vitro. After confirming the phenotype and differentiation capacity of the isolated cells, we infected the cells in vitro with HSV1-KOS, HSV1-532 and HSV2 virus strains. Twenty-four hours after infection, we examined the gene expression of the cells via RNA-seq and RT-PCR; detected secreted cytokines via protein array; and determined autophagy via Western blot, transmission electron microscopy (TEM) and fluorescence microscopy. Infection with different HSV strains resulted in different gene-expression patterns. In addition to the activation of pathways characteristic of viral infections, distinct non-immunological pathways (autophagy, tissue regeneration and differentiation) were also activated according to analyses with QIAGEN Ingenuity Pathway Analysis, Kyoto Encyclopedia of Genes and Genome and Genome Ontology Enrichment. Viral infections increased autophagy, as confirmed via TEM image analysis, and also increased levels of the microtubule-associated protein light chain 3 (LC3B) II protein. We identified significantly altered accumulation for 16 cytokines involved in tissue regeneration and inflammation. Our studies demonstrated that HSV infection can alter the viability and immunological status of ADMSCs, which may have implications for ADMSC-based cell therapies. Alterations in autophagy can affect numerous processes in MSCs, including the inhibition of tissue regeneration as well as pathological differentiation.
Topics: Humans; Herpesvirus 1, Human; Herpes Simplex; Mesenchymal Stem Cells; Herpesvirus 2, Human; Cytokines; Inflammation
PubMed: 37569367
DOI: 10.3390/ijms241511989 -
Journal of Clinical Virology : the... Aug 2023The recent mpox outbreak has highlighted the need to rapidly diagnose the causative agents of viral vesicular disease to inform treatment and control measures. Common...
BACKGROUND
The recent mpox outbreak has highlighted the need to rapidly diagnose the causative agents of viral vesicular disease to inform treatment and control measures. Common causes of vesicular disease include Monkeypox virus (MPXV), clades I and II, Herpes simplex viruses Type 1 and Type 2 (HSV-1, HSV-2), human herpes virus 6 (HHV-6), Varicella-zoster virus (VZV) and Enteroviruses (EVs). Here, we assessed a syndromic viral vesicular panel for rapid and simultaneous detection of these 7 targets in a single cartridge.
OBJECTIVE
The aim of this study was to evaluate the QIAStat-Dx ® viral vesicular (VV) panel and compare with laboratory developed tests (LDTs). Limit of detection, inter-run variability, cross-reactivity and specificity were assessed. Positive and negative percent agreement, and correlation between assays was determined using 124 clinical samples from multiple anatomical sites.
RESULTS
The overall concordance between the QIAstat and LDTs was 96%. Positive percent agreement was 82% for HHV-6, 89% for HSV-1 and 100% for MPXV, HSV-2, EV and VZV. Negative percent agreement was 100% for all targets assessed. There was no cross-reactivity with Vaccinia, Orf, Molluscum contagiosum viruses, and a pooled respiratory panel.
CONCLUSION
The QIAstat VV multi-target syndromic panel combine ease of use, rapid turnaround, good sensitivity and specificity for enhanced diagnosis, clinical care and public health responses.
Topics: Humans; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Herpesvirus 3, Human; Herpesvirus 6, Human; Virus Diseases; Viruses; Monkeypox virus
PubMed: 37364498
DOI: 10.1016/j.jcv.2023.105525 -
Viruses Aug 2021Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and... (Review)
Review
Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed "latency", which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines' "rational" design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.
Topics: Animals; Drug Design; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Vaccines, Attenuated; Viral Vaccines
PubMed: 34452501
DOI: 10.3390/v13081637 -
Journal of Virology Mar 2023Type I interferon (IFN-I) response plays a prominent role in innate immunity, which is frequently modulated during viral infection. Here, we report DNA methylation...
Type I interferon (IFN-I) response plays a prominent role in innate immunity, which is frequently modulated during viral infection. Here, we report DNA methylation regulator UHRF1 as a potent negative regulator of IFN-I induction during alphaherpesvirus infection, whereas the viruses in turn regulates the transcriptional expression of UHRF1. Knockdown of UHRF1 in cells significantly increases interferon-β (IFN-β)-mediated gene transcription and viral inhibition against herpes simplex virus 1 (HSV1) and pseudorabies virus (PRV). Mechanistically, UHRF1 deficiency promotes IFN-I production by triggering dsRNA-sensing receptor RIG-I and activating IRF3 phosphorylation. Knockdown of UHRF1 in cells upregulates the accumulation of double-stranded RNA (dsRNA), including host endogenous retroviral sequence (ERV) transcripts, while the treatment of RNase III, known to specifically digest dsRNA, prevents IFN-β induction by siUHRF1. Furthermore, the double-knockdown assay of UHRF1 and DNA methyltransferase DNMT1 suggests that siUHRF1-mediated DNA demethylation may play an important role in dsRNA accumulation and subsequently IFN induction. These findings establish the essential role of UHRF1 in IFN-I-induced antiviral immunity and reveal UHRF1 as a potential antivrial target. Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals, which rely partly on their interaction with IFN-mediated innate immune response. Using alphaherpesviruses PRV and HSV-1 as models, we identified an essential role of DNA methylation regulator UHRF1 in IFN-mediated immunity against virus replication, which unravels a novel mechanism employed by epigenetic factor to control IFN-mediated antiviral immune response and highlight UHRF1, which might be a potential target for antiviral drug development.
Topics: Animals; Humans; Antiviral Agents; CCAAT-Enhancer-Binding Proteins; Gene Expression; Herpesvirus 1, Human; Herpesvirus 1, Suid; Immunity, Innate; Interferon Regulatory Factor-3; Interferon Type I; Interferon-beta; Ubiquitin-Protein Ligases; Alphaherpesvirinae; Receptors, Immunologic
PubMed: 36916938
DOI: 10.1128/jvi.00134-23 -
Current Issues in Molecular Biology 2021Both the development of the mammalian innate immune system and the antagonistic strategies acquired by alphaherpesviruses to dismantle it have been shaped by co-evolving... (Review)
Review
Both the development of the mammalian innate immune system and the antagonistic strategies acquired by alphaherpesviruses to dismantle it have been shaped by co-evolving virus-host interactions over millions of years. Here, we review mechanisms employed by mammalian cells to detect pathogen molecules, such as viral glycoproteins and nucleic acids, and induce innate immune signaling upon infection with alphaherpesviruses. We further explore strategies acquired by these viruses to bypass immune detection and activation, thereby supporting virus replication and spread. Finally, we discuss the contributions of advanced 'omics' and microscopy methods to these discoveries in immune signaling and highlight emerging technologies that can help to further our understanding of the dynamic interplay between host innate immune responses and virus immune evasion.
Topics: Alphaherpesvirinae; Animals; Biological Evolution; DNA, Viral; Herpesviridae Infections; Host-Pathogen Interactions; Humans; Immune Evasion; Immunity, Innate; Signal Transduction; Viral Proteins; Virus Replication
PubMed: 33640867
DOI: 10.21775/cimb.042.635