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Herpes Type 1 (HSV1), Clone FHV5, Mab anti_Cat; frozen_paraffin, IH_ELISA

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[#YSRTMCA2195] Herpes Type 1 (HSV1), Clone FHV5, Mab anti_Cat; frozen_paraffin, IH_ELISA


YSRTMCA2195 | Herpes Type 1 (HSV1), Clone FHV5, Mab anti_Cat; frozen_paraffin, IH_ELISA, 0.25 mg.
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(1) Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection.[TOP]

Pubmed ID :30154162
Publication Date : //
Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/β- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-β but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/β receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.

Authors : Zimmer Bastian, Ewaleifoh Osefame, Harschnitz Oliver, Lee Yoon-Seung, Peneau Camille, McAlpine Jessica L, Liu Becky, Tchieu Jason, Steinbeck Julius A, Lafaille Fabien, Volpi Stefano, Notarangelo Luigi D, Casanova Jean-Laurent, Zhang Shen-Ying, Smith Gregory A, Studer Lorenz,

(2) Prevalence of HSV1/2 Congenital Infection Assessed Through Genome Detection on Dried Blood Spot in Individuals with Autism Spectrum Disorders.[TOP]

Pubmed ID :30150453
Publication Date : //
Etiopathogenesis of autism spectrum disorders (ASD) remains to be elucidated. Congenital infections, particularly viral infections, have repeatedly been associated with the onset of such disorders. Our study aimed at assessing the prevalence of herpes simplex type 1 and 2 (HSV1/2) congenital infections in patients with ASD.

Authors : Zappulo Emanuela, Riccio Maria Pia, Binda Sandro, Pellegrinelli Laura, Pregliasco Fabrizio, Buonomo Antonio Riccardo, Pinchera Biagio, D'Urso Giordano, Bravaccio Carmela, Borgia Guglielmo, Gentile Ivan,

(3) HSV1/2 Genital Infection in Mice Cause Reversible Delayed Gastrointestinal Transit: A Model for Enteric Myopathy.[TOP]

Pubmed ID :30065927
Publication Date : //
In an interesting investigation by Khoury-Hanold et al. (1), genital infection of mice with herpes simplex virus 1 (HSV1) were reported to cause multiple pelvic organ involvement and obstruction. A small subset of mice succumbed after the first week of HSV1 infection. The authors inferred that the mice died due to toxic megacolon. In a severe form of mechanical and/or functional obstruction involving gross dilation of the colon and profound toxemia, the presentation is called "toxic megacolon." The representative observations by Khoury-Hanold likely do not resemble toxic megacolon. The colon was only slightly dilated and benign appearing. Importantly, HSV1 infection affected the postjunctional mechanisms of smooth muscle relaxation like the sildenafil-response proteins, which may have been responsible for defective nitrergic neurotransmission and the delayed transit. Orally administered polyethylene glycol reversed the gastrointestinal "obstruction," suggesting a mild functional type of slowed luminal transit, resembling constipation, rather than toxic megacolon, which cannot be reversed by an osmotic laxative without perforating the gut. The authors suggest that the mice did not develop HSV1 encephalitis, the commonly known cause of mortality. The premature death of some of the mice could be related to the bladder outlet obstruction, whose backflow effects may alter renal function, electrolyte abnormalities and death. Muscle strip recordings of mechanical relaxation after electrical field stimulation of gastrointestinal, urinary bladder or cavernosal tissues shall help obtain objective quantitative evidence of whether HSV infection indeed cause pelvic multi-organ dysfunction and impairment of autonomic neurotransmission and postjunctional electromechanical relaxation mechanisms of these organs.

Authors : Chaudhury Arun, Dendi Vijaya Sena Reddy, Chaudhury Mousumi, Jain Astha, Kasarla Madhukar Reddy, Panuganti Kiran, Jain Gaurav, Ramanujam Abhijit, Rena Bhavin, Koyagura Sudheer Reddy, Fogla Sumit, Kumar Sunil, Shekhawat Nawal Singh, Maddur Srinivas,

(4) Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity.[TOP]

Pubmed ID :29997210
Publication Date : //
Type I interferons (IFNs), as major components of the innate immune system, play a vital role in host resistance to a variety of pathogens. Canonical signaling mediated by type I IFNs activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway through binding to the IFN-α/β receptor (IFNAR), resulting in transcription of IFN-stimulated genes (ISGs). However, viruses have evolved multiple strategies to evade this process. Here, we report that herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates the type I IFN-mediated signaling pathway independent of its deubiquitinase (DUB) activity. In this study, ectopically expressed UL36USP inhibited IFN-β-induced activation of ISRE promoter and transcription of ISGs, and overexpression of UL36USP lacking DUB activity did not influence this effect. Furthermore, UL36USP was demonstrated to antagonize IFN-β-induced activation of JAKs and STATs via specifically binding to the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2. More importantly, knockdown of HSV-1 UL36USP restored the formation of JAK1-IFNAR2 complex. These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated signaling pathway and reveal a novel evasion mechanism of antiviral innate immunity by HSV-1. Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN-mediated signaling. UL36USP was identified to significantly inhibit IFN-β-induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN-mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay.

Authors : Yuan Hui, You Jia, You Hongjuan, Zheng Chunfu,

(5) Roles of the Phosphorylation of Herpes Simplex Virus 1 UL51 at a Specific Site in Viral Replication and Pathogenicity.[TOP]

Pubmed ID :29976672
Publication Date : //
Herpes simplex virus 1 (HSV-1) UL51 is a phosphoprotein that functions in the final envelopment in the cytoplasm and viral cell-cell spread, leading to efficient viral replication in cell cultures. To clarify the mechanism by which UL51 is regulated in HSV-1-infected cells, we focused on the phosphorylation of UL51. Mass spectrometry analysis of purified UL51 identified five phosphorylation sites in UL51. Alanine replacement of one of the identified phosphorylation sites in UL51, serine 184 (Ser-184), but not the other identified phosphorylation sites, significantly reduced viral replication and cell-cell spread in HaCaT cells. This mutation induced membranous invaginations adjacent to the nuclear membrane, the accumulation of primary enveloped virions in the invaginations and perinuclear space, and mislocalized UL34 and UL31 in punctate structures at the nuclear membrane; however, it had no effect on final envelopment in the cytoplasm of HaCaT cells. Of note, the alanine mutation in UL51 Ser-184 significantly reduced the mortality of mice following ocular infection. Phosphomimetic mutation in UL51 Ser-184 partly restored the wild-type phenotype in cell cultures and in mice. Based on these results, we concluded that some UL51 functions are specifically regulated by phosphorylation at Ser-184 and that this regulation is critical for HSV-1 replication in cell cultures and pathogenicity HSV-1 UL51 is conserved in all members of the family. This viral protein is phosphorylated and functions in viral cell-cell spread and cytoplasmic virion maturation in HSV-1-infected cells. Although the downstream effects of HSV-1 UL51 have been clarified, there is a lack of information on how this viral protein is regulated as well as the significance of the phosphorylation of this protein in HSV-1-infected cells. In this study, we show that the phosphorylation of UL51 at Ser-184 promotes viral replication, cell-cell spread, and nuclear egress in cell cultures and viral pathogenicity in mice. This is the first report to identify the mechanism by which UL51 is regulated as well as the significance of UL51 phosphorylation in HSV-1 infection. Our study may provide insights into the regulatory mechanisms of other herpesviral UL51 homologs.

Authors : Kato Akihisa, Oda Shinya, Watanabe Mizuki, Oyama Masaaki, Kozuka-Hata Hiroko, Koyanagi Naoto, Maruzuru Yuhei, Arii Jun, Kawaguchi Yasushi,

(6) The Apical Region of the Herpes Simplex Virus Major Capsid Protein Promotes Capsid Maturation.[TOP]

Pubmed ID :29976665
Publication Date : //
The herpesvirus capsid assembles in the nucleus as an immature procapsid precursor built around viral scaffold proteins. The event that initiates procapsid maturation is unknown, but it is dependent upon activation of the VP24 internal protease. Scaffold cleavage triggers angularization of the shell and its decoration with the VP26 and pUL25 capsid-surface proteins. In both the procapsid and mature angularized capsid, the apical region of the major capsid protein (VP5) is surface exposed. We investigated whether the VP5 apical region contributes to intracellular transport dynamics following entry into primary sensory neurons and also tested the hypothesis that conserved negatively charged amino acids in the apical region contribute to VP26 acquisition. To our surprise, neither hypothesis proved true. Instead, mutation of glutamic acid residues in the apical region delayed viral propagation and induced focal capsid accumulations in nuclei. Examination of capsid morphogenesis based on epitope unmasking, capsid composition, and ultrastructural analysis indicated that these clusters consisted of procapsids. The results demonstrate that, in addition to established events that occur inside the capsid, the exterior capsid shell promotes capsid morphogenesis and maturation. Herpesviruses assemble capsids and encapsidate their genomes by a process that is unlike those of other mammalian viruses but is similar to those of some bacteriophage. Many important aspects of herpesvirus morphogenesis remain enigmatic, including how the capsid shell matures into a stable angularized configuration. Capsid maturation is triggered by activation of a protease that cleaves an internal protein scaffold. We report on the fortuitous discovery that a region of the major capsid protein that is exposed on the outer surface of the capsid also contributes to capsid maturation, demonstrating that the morphogenesis of the capsid shell from its procapsid precursor to the mature angularized form is dependent upon internal and external components of the megastructure.

Authors : Ruhge Laura L, Huet Alexis G E, Conway James F, Smith Gregory A,

(7) Extracellular Vesicles Released by Herpes Simplex Virus 1-Infected Cells Block Virus Replication in Recipient Cells in a STING-Dependent Manner.[TOP]

Pubmed ID :29976662
Publication Date : //
Herpes simplex virus 1 (HSV-1)-infected cells release extracellular vesicles (EVs) that deliver to uninfected cells viral factors and host components, such as the stimulator of interferon genes (STING), which activates type I interferon upon foreign DNA sensing. The functions of EVs released by HSV-1-infected cells have remained unknown. Here, we describe a procedure to separate the EVs from HSV-1 virions that is based on an iodixanol/sucrose gradient. STING, along with the EV markers CD63 and CD9, was found in light-density fractions, while HSV components accumulated in heavy-density fractions. HSV-1 infection stimulated the release of EVs from the cells. The EVs derived from infected cells, but not from uninfected cells, activated innate immunity in recipient cells and suppressed viral gene expression and virus replication. Moreover, only the EVs derived from infected cells stimulated the expression of a subset of M1-type markers in recipient macrophages. Conversely, EVs derived from STING-knockdown cells failed to stimulate the expression of these M1-type markers, they activated innate immune responses to a lesser extent in recipient cells, and they did not sustain the inhibition of virus replication. These data suggest that STING from the EV donor cells contributes to the antiviral responses in cells receiving EVs from HSV-1-infected cells. Perturbations in the biogenesis of EVs by silencing CD63 or blocking the activity of the neutral spingomyelinase-2 (nSMase-2) increased the HSV-1 yields. Overall, our data suggest that the EVs released from HSV-1-infected cells negatively impact the infection and could control the dissemination of the virus. Extracellular vesicles (EVs) are released by all types of cells as they constitute major mechanism of intercellular communication and have the capacity to alter the functions of recipient cells despite their limited capacity for cargo. How the EVs released by HSV-infected cells could alter the surrounding microenvironment and influence the infection currently remains unknown. The cargo of EVs reflects the physiological state of the cells in which they were produced, so the content of EVs originating from infected cells is expected to be substantially different from that of healthy cells. Our studies indicate that the EVs released by HSV-1-infected cells carry innate immune components such as STING and other host and viral factors; they can activate innate immune responses in recipient cells and inhibit HSV-1 replication. The implication of these data is that the EVs released by HSV-1-infected cells could control HSV-1 dissemination promoting its persistence in the host.

Authors : Deschamps Thibaut, Kalamvoki Maria,

(8) Cellular Antisilencing Elements Support Transgene Expression from Herpes Simplex Virus Vectors in the Absence of Immediate Early Gene Expression.[TOP]

Pubmed ID :29950408
Publication Date : //
Inactivation of all herpes simplex virus (HSV) immediate early (IE) genes to eliminate vector cytotoxicity results in rapid silencing of the viral genome, similar to the establishment of HSV latency. We recently reported that silencing of a nonviral reporter cassette could be overcome in nonneuronal cells by positioning the cassette in the viral latency (LAT) locus between resident chromatin boundary elements. Here, we tested the abilities of the chicken hypersensitive site 4 insulator and the human ubiquitous chromatin opening element A2UCOE to promote transgene expression from an IE-gene-inactivated HSV vector. We found that A2UCOE was particularly active in nonneuronal cells and reduced reporter promoter occupancy by a repressive histone mark. We determined whether multiple transgenes could be expressed under the control of different promoters from different loci of the same virus. The results showed abundant coexpression of LAT-embedded and A2UCOE-flanked genes in nonneuronal cells. In addition, a third reporter gene without known protective elements was active in cultured rat sensory neurons. These findings indicate that cellular antisilencing sequences can contribute to the expression of multiple genes from separate promoters in fully IE gene-disabled HSV vectors, providing an opportunity for therapeutic applications requiring mutually independent expression of different gene products from a single vector. Gene therapy has now entered a phase of development in which a growing number of recessive single gene defects can be successfully treated by vector-mediated introduction of a wild-type copy of the gene into the appropriate tissue. However, many disease conditions, such as neurodegeneration, cancer, and inflammatory processes, are more complex, requiring either multiple gene corrections or provision of coordinated gene activities to achieve a therapeutic outcome. Although herpes simplex virus (HSV) vectors have the capacity to meet this need, the challenge has been to genetically engineer the HSV genome in a manner to prevent expression of any viral genes while retaining the ability to express multiple therapeutic transgenes under independent transcriptional control. Here, we show that non-HSV insulator elements can be applied to retain at least transient transgene activity from multiple viral loci, thereby opening the door for more complex gene therapy applications in the future.

Authors : Han Fang, Miyagawa Yoshitaka, Verlengia Gianluca, Ingusci Selene, Soukupova Marie, Simonato Michele, Glorioso Joseph C, Cohen Justus B,

(9) Attenuated Herpes Simplex Virus 1 (HSV-1) Expressing a Mutant Form of ICP6 Stimulates a Strong Immune Response That Protects Mice against HSV-1-Induced Corneal Disease.[TOP]

Pubmed ID :29950407
Publication Date : //
We previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations in , resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0, ICP8, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8 virus, but not the ICP0 virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases. HSV-1 is a ubiquitous human pathogen that infects the majority of the world's population. Although most infections are asymptomatic, HSV-1 establishes lifelong latency in infected sensory neurons, from which it can reactivate to cause deadly encephalitis or potentially blinding eye disease. No clinically effective vaccine is available. In this study, we tested the protective potential of a neuroattenuated HSV-1 mutant (KOS-NA) as a vaccine in mice. We compared the effects of immunization with KOS-NA to those of two other attenuated viruses, a replication-competent (ICP0) virus and a replication-incompetent (ICP8) virus. Our data show that KOS-NA proved superior to the ICP0- and ICP8-null mutants in protecting mice from corneal disease and latent infection. With its significant neuroattenuation, severe impairment in establishing latency, and excellent protective effect, KOS-NA represents a significant discovery in the field of HSV-1 vaccine development.

Authors : Davido David J, Tu Eleain M, Wang Hong, Korom Maria, Gazquez Casals Andreu, Reddy P Jahnu, Mostafa Heba H, Combs Benjamin, Haenchen Steve D, Morrison Lynda A,

(10) Multiple post-transcriptional strategies to regulate the herpes simplex virus type 1 vhs endoribonuclease.[TOP]

Pubmed ID :29925667
Publication Date : //
The HSV1 virion host shutoff (vhs) protein is an endoribonuclease that binds to the cellular translation initiation machinery and degrades associated mRNAs, resulting in shut-off of host protein synthesis. Hence its unrestrained activity is considered to be lethal, and it has been proposed that vhs is regulated by two other virus proteins, VP22 and VP16. We have found that during infection, translation of vhs requires VP22 but not the VP22-VP16 complex. Moreover, in the absence of VP22, vhs is not overactive against cellular or viral transcripts. In transfected cells, vhs was also poorly translated, correlating with aberrant localization of its mRNA. Counterintuitively, vhs mRNA was predominantly nuclear in cells where vhs protein was detected. Likewise, transcripts from co-transfected plasmids were also retained in the same nuclei where vhs mRNA was located, while polyA binding protein (PABP) was relocalised to the nucleus in a vhs-dependent manner, implying a general block to mRNA export. Co-expression of VP16 and VP22 rescued cytoplasmic localization of vhs mRNA but failed to rescue vhs translation. We identified a 230-nucleotide sequence in the 5' region of vhs that blocked its translation and, when transferred to a heterologous GFP transcript, reduced translation without altering mRNA levels or localization. We propose that expression of vhs is tightly regulated by a combination of inherent untranslatability and auto-induced nuclear retention of its mRNA that results in a negative feedback loop, with nuclear retention but not translation of vhs mRNA being the target of rescue by the vhs-VP16-VP22 complex. A myriad of gene expression strategies has been discovered through studies carried out on viruses. This report concerns the regulation of the HSV1 vhs endoribonuclease, a virus factor that is important for counteracting host antiviral responses by degrading their mRNAs, but which must be regulated during infection to ensure that it does not act against and inhibit the virus itself. We show that regulation of vhs involves multifaceted post-transcriptional cellular and viral processes, including aberrant mRNA localization and a novel, autoregulated negative feedback loop to target its own and co-expressed mRNAs for nuclear retention, an activity that is relieved by co-expression of two other virus proteins, VP22 and VP16. These studies reveal the interplay of strategies by which multiple virus-encoded factors co-ordinate gene expression at the time they are needed. These findings are broadly relevant to both virus and cellular gene expression.

Authors : Elliott Gillian, Pheasant Kathleen, Ebert-Keel Katja, Stylianou Julianna, Franklyn Ashley, Jones Juliet,