UL24 herpesvirus determinants of pathogenesis: Roles in virus-host interactions.

Members of the UL24 herpesvirus gene family are determinants of pathogenesis. The gene is widely conserved across the Orthoherpesviridae family, also commonly referred to as Herpesviridae. In this review, the impact of UL24 homologs on pathogenesis as studied with different model systems is presented, as well as mechanistic aspects related to the different roles of UL24 proteins in virus-host cell interactions.

Small RNA sequencing analysis reveals regulation of microRNA expression in Madin-Darby canine kidney epithelial cells infected with Canid alphaherpesvirus 1.

Canid alphaherpesvirus 1 (CHV-1) infection can cause spontaneous abortions in pregnant dams, and in young puppies, fatal systemic infections are common. MicroRNAs (miRNAs) affect viral infection by binding to messenger RNAs, and inhibiting expression of host and/or viral genes. We conducted deep sequencing of small RNAs in CHV-1-infected and mock-infected Madin-Darby Canine Kidney (MDCK) epithelial cells, and detected sequences corresponding to 282 cellular miRNAs.

Identification of glycosylated nucleosides in small synthetic glyco-RNAs.

Recently, the post-transcriptional modification of RNA with N-glycans was reported, changing the paradigm that RNAs are not commonly N-glycosylated. Moreover, glycan modifications of RNA are investigated for therapeutic targeting purposes. But the glyco-RNA field is in its infancy with many challenges to overcome.

The Disruption of a Nuclear Export Signal in the C-Terminus of the Herpes Simplex Virus 1 Determinant of Pathogenicity UL24 Protein Leads to a Syncytial Plaque Phenotype.

of herpes simplex virus 1 (HSV-1) has been shown to be a determinant of pathogenesis in mouse models of infection. The N-terminus of UL24 localizes to the nucleus and drives the redistribution of nucleolin and B23. In contrast, when expressed alone, the C-terminal domain of UL24 accumulates in the Golgi apparatus; its importance during infection is unknown.

Preferentially Infects Polarized Madin-Darby Canine Kidney Cells from the Basolateral Surface.

(CHV-1) infects polarized canine epithelia. Herein, we present our initial work characterizing CHV-1 infection of Madin-Darby canine kidney (MDCK) cells that were polarized on trans-wells. We previously showed that infection of these cells in non-polarized cultures stimulated the formation of extensive lamellipodial membrane protrusions.

Entry of the Varicellovirus Canid herpesvirus 1 into Madin-Darby canine kidney epithelial cells is pH-independent and occurs via a macropinocytosis-like mechanism but without increase in fluid uptake.

Canid herpesvirus 1 (CHV-1) is a Varicellovirus that causes self-limiting infections in adult dogs but morbidity and mortality in puppies. Using a multipronged approach, we discovered the CHV-1 entry pathway into Madin-Darby canine kidney (MDCK) epithelial cells. We found that CHV-1 triggered extensive host cell membrane lamellipodial ruffling and rapid internalisation of virions in large, uncoated vacuoles, suggestive of macropinocytosis.

-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis.

Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the gene ( ), encoding for the NF-κB transcription factor subunit c-Rel.

A Mutation in the Gene Abolishes Expression of the Newly Identified UL24.5 Protein of Herpes Simplex Virus 1 and Leads to an Increase in Pathogenicity in Mice.

Herpes simplex virus 1 (HSV-1) infects the host via epithelia and establishes latency in sensory neurons. The gene is conserved throughout the family, and the UL24 protein is important for efficient viral replication and pathogenesis. Multiple transcripts are expressed from the gene.

Herpes simplex virus 1 infection of T cells causes VP11/12-dependent phosphorylation and degradation of the cellular protein Dok-2.

Previous studies have shown that HSV-1 infection of lymphocytes induces the tyrosine phosphorylation of several proteins that might correspond to viral or host proteins. VP11/12, a viral tegument protein, is the major HSV-induced tyrosine phosphorylated protein identified thus far. In this report, we demonstrated that the cellular adaptor proteins Dok-2 and Dok-1 are tyrosine phosphorylated upon HSV-1 infection.

Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8 T Cells in a Murine Model of Ocular Infection.

Dok-1 and Dok-2 negatively regulate responses downstream of several immune receptors in lymphoid and myeloid cells. Recent evidence showed that Dok proteins are essential in the formation of memory CD8 T cells to an exogenous epitope expressed by vaccinia virus; however, the importance of Dok-1 and Dok-2 in the control of viral infection is unknown. Here, we investigated the role of Dok proteins in modulating the immune response against herpes simplex virus 1 (HSV-1) in a mouse model of ocular infection.

Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-κB Activation.

Cyclic GMP-AMP synthase (cGAS) is a newly identified DNA sensor that recognizes foreign DNA, including the genome of herpes simplex virus 1 (HSV-1). Upon binding of viral DNA, cGAS produces cyclic GMP-AMP, which interacts with and activates stimulator of interferon genes (STING) to trigger the transcription of antiviral genes such as type I interferons (IFNs), and the production of inflammatory cytokines. HSV-1 UL24 is widely conserved among members of the herpesviruses family and is essential for efficient viral replication.

Regulation of viral gene expression by the herpes simplex virus 1UL24 protein (HSV-1UL24 inhibits accumulation of viral transcripts).

UL24 is conserved among all Herpesviridae. In herpes simplex virus 1 (HSV-1), UL24 mutations lead to reduced viral titers both in cell culture and in vivo, and reduced pathogenicity. The human cytomegalovirus ortholog of UL24 has a gene regulatory function; however, it is not known whether other UL24 orthologs also affect gene expression.

Identification of Risk Factors for Chemotherapy-Related 30-Day Readmissions.

Purpose: The goal of this study was to develop a method for practitioners to evaluate both quality of care delivered to patients receiving chemotherapy and illicit risk factors for 30-day chemotherapy-related readmissions (CRR).

Methods: Midas+ DataVision Readmission Tool Pack (Version 2.x) was used to retrospectively identify patients who received inpatient chemotherapy from April 2010 through May 2013.

Mutation of UL24 impedes the dissemination of acute herpes simplex virus 1 infection from the cornea to neurons of trigeminal ganglia.

Herpes simplex virus 1 (human herpesvirus 1) initially infects epithelial cells of the mucosa and then goes on to infect sensory neurons leading ultimately to a latent infection in trigeminal ganglia (TG). UL24 is a core herpesvirus gene that has been identified as a determinant of pathogenesis in several Alphaherpesvirinae, although the underlying mechanisms are unknown. In a mouse model of ocular infection, a UL24-deficient virus exhibited a reduction in viral titres in tear films of 1 log10, whilst titres in TG are often below the level of detection.

Upstream binding factor inhibits herpes simplex virus replication.

Herpes simplex virus 1 (HSV-1) infection induces changes to the host cell nucleus including relocalization of the cellular protein Upstream Binding Factor (UBF) from the nucleolus to viral replication compartments (VRCs). Herein, we tested the hypothesis that UBF is recruited to VRCs to promote viral DNA replication. Surprisingly, infection of UBF-depleted HeLa cells with HSV-1 or HSV-2 produced higher viral titers compared to controls.

Visualization of mouse neuronal ganglia infected by Herpes Simplex Virus 1 (HSV-1) using multimodal non-linear optical microscopy.

Herpes simplex virus 1 (HSV-1) is a neurotropic virus that causes skin lesions and goes on to enter a latent state in neurons of the trigeminal ganglia. Following stress, the virus may reactivate from latency leading to recurrent lesions. The in situ study of neuronal infections by HSV-1 is critical to understanding the mechanisms involved in the biology of this virus and how it causes disease; however, this normally requires fixation and sectioning of the target tissues followed by treatment with contrast agents to visualize key structures, which can lead to artifacts.

The UL24 protein of herpes simplex virus 1 affects the sub-cellular distribution of viral glycoproteins involved in fusion.

Mutations in UL24 of herpes simplex virus type 1 can lead to a syncytial phenotype. We hypothesized that UL24 affects the sub-cellular distribution of viral glycoproteins involved in fusion. In non-immortalized human foreskin fibroblasts (HFFs) we detected viral glycoproteins B (gB), gD, gH and gL present in extended blotches throughout the cytoplasm with limited nuclear membrane staining; however, in HFFs infected with a UL24-deficient virus (UL24X), staining for the viral glycoproteins appeared as long, thin streaks running across the cell.

The ribonucleotide reductase R1 subunits of herpes simplex virus 1 and 2 protect cells against poly(I · C)-induced apoptosis.

We recently provided evidence that the ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 (HSV-1 and -2) protect cells against tumor necrosis factor alpha- and Fas ligand-induced apoptosis by interacting with caspase 8. Double-stranded RNA (dsRNA) is a viral intermediate known to initiate innate antiviral responses. Poly(I · C), a synthetic analogue of viral dsRNA, rapidly triggers caspase 8 activation and apoptosis in HeLa cells.

Involvement of the UL24 protein in herpes simplex virus 1-induced dispersal of B23 and in nuclear egress.

UL24 of herpes simplex virus 1 (HSV-1) is widely conserved within the Herpesviridae family. Herein, we tested the hypothesis that UL24, which we have previously shown to induce the redistribution of nucleolin, also affects the localization of the nucleolar protein B23. We found that HSV-1-induced dispersal of B23 was dependent on UL24.

Relocalization of upstream binding factor to viral replication compartments is UL24 independent and follows the onset of herpes simplex virus 1 DNA synthesis.

Herpes simplex virus 1 (HSV-1) induces relocalization of several nucleolar proteins. We have found that, as for fibrillarin, the HSV-1-induced redistribution of two RNA polymerase I components, upstream binding factor (UBF) and RPA194, was independent of the viral protein UL24, which affects nucleolin localization. Nevertheless, the kinetics and sites of redistribution for fibrillarin and UBF differed.

Differential importance of highly conserved residues in UL24 for herpes simplex virus 1 replication in vivo and reactivation.

The UL24 gene of herpes simplex virus 1 (HSV-1) is widely conserved among all subfamilies of the Herpesviridae. It is one of only four HSV-1 genes for which mutations have been mapped that confer a syncytial plaque phenotype. In a mouse model of infection, UL24-deficient viruses exhibit reduced titres, particularly in neurons, and an apparent defect in reactivation from latency.

Conserved residues in the UL24 protein of herpes simplex virus 1 are important for dispersal of the nucleolar protein nucleolin.

The UL24 family of proteins is widely conserved among herpesviruses. We demonstrated previously that UL24 of herpes simplex virus 1 (HSV-1) is important for the dispersal of nucleolin from nucleolar foci throughout the nuclei of infected cells. Furthermore, the N-terminal portion of UL24 localizes to nuclei and can disperse nucleolin in the absence of any other viral proteins.

The conserved N-terminal domain of herpes simplex virus 1 UL24 protein is sufficient to induce the spatial redistribution of nucleolin.

UL24 is widely conserved among herpesviruses but its function during infection is poorly understood. Previously, we discovered a genetic link between UL24 and the herpes simplex virus 1-induced dispersal of the nucleolar protein nucleolin. Here, we report that in the absence of viral infection, transiently expressed UL24 accumulated in both the nucleus and the Golgi apparatus.

Involvement of UL24 in herpes-simplex-virus-1-induced dispersal of nucleolin.

UL24 of herpes simplex virus 1 is important for efficient viral replication, but its function is unknown. We generated a recombinant virus, vHA-UL24, encoding UL24 with an N-terminal hemagglutinin tag. By indirect immunofluorescence at 9 h post-infection (hpi), we detected HA-UL24 in nuclear foci and in cytoplasmic speckles.