ABSTRACT
Varicella-zoster virus (VZV), a common pathogen with humans as the sole host, causes primary infection and undergoes a latent period in sensory ganglia. The recurrence of VZV is often accompanied by severe neuralgia in skin tissue, which has a serious impact on the life of patients. During the acute infection of VZV, there are few related studies on the pathophysiological mechanism of skin tissue. In this study, transcriptome sequencing data from the acute response period within 2 days of VZV antigen stimulation of the skin were used to explore a model of the trajectory of skin tissue changes during VZV infection. It was found that early VZV antigen stimulation caused activation of mainly natural immune-related signaling pathways, while in the late phase activation of mainly active immune-related signaling pathways. JAK-STAT, NFκB, and TNFα signaling pathways are gradually activated with the progression of infection, while Hypoxia is progressively inhibited. In addition, we found that dendritic cell-mediated immune responses play a dominant role in the lesion damage caused by VZV antigen stimulation of the skin. This study provides a theoretical basis for the study of the molecular mechanisms of skin lesions during acute VZV infection.
Subject(s)
Herpesvirus 3, Human , Signal Transduction , Skin , Varicella Zoster Virus Infection , Herpesvirus 3, Human/genetics , Skin/pathology , Skin/virology , Skin/immunology , Animals , Varicella Zoster Virus Infection/virology , Varicella Zoster Virus Infection/immunology , Varicella Zoster Virus Infection/genetics , Varicella Zoster Virus Infection/pathology , Humans , Mice , Dendritic Cells/immunology , Herpes Zoster/virology , Herpes Zoster/pathology , Herpes Zoster/genetics , Herpes Zoster/immunology , Transcriptome , Disease Models, Animal , Antigens, Viral/immunology , Antigens, Viral/genetics , NF-kappa B/metabolism , NF-kappa B/geneticsABSTRACT
Background: Previous observational or retrospective studies have suggested an association between inflammatory bowel disease (IBD) and herpes virus infections. Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between IBD and herpes virus infections. Methods: In genome-wide association study (GWAS) datasets of the International Inflammatory Bowel Disease Genetics Consortium, we obtained genetic instrumental variables for three phenotypes from 34,652 participants (12,882 IBD cases and 21,770 controls), 27,432 participants [6,968 ulcerative colitis (UC) cases and 20,464 controls], and 20,883 participants [5,956 Crohn's disease (CD) cases and 14,927 controls], respectively. Summary statistics for herpes virus infections (chickenpox, herpes zoster, and mononucleosis) were obtained from the FinnGen database. MR results were expressed as odds ratio (OR) with 95% confidence interval (CI). Results: Our study found no evidence of a causal effect of genetically predicted IBD on herpes virus infections [P value for inverse variance weighting (IVW): 0.063 to 0.652]. For the subtypes of IBD, UC had a suggestive association with mononucleosis (P value for IVW: 0.023). It appeared that CD was also weakly associated with mononucleosis (P value for IVW: 0.058; P value for Weighted median: 0.036). In addition, we found a suggestive causality for CD on chickenpox (P value for IVW: 0.038). Neither UC (P value for IVW: 0.574) nor CD (P value for IVW: 0.168) has a causal effect on herpes zoster. The results of the bidirectional MR analysis did not indicate that herpes virus infections were associated with IBD, UC or CD (P value for IVW: 0.239 to 0.888). Conclusion: This study showed a suggestive causality for both CD-chickenpox and UC-mononucleosis, despite no associations reaching a statistical significance value after corrections for multiple testing. There was no evidence of a causal association between IBD and its two subtypes on herpes zoster.
Subject(s)
Chickenpox , Colitis, Ulcerative , Crohn Disease , Herpes Zoster , Infectious Mononucleosis , Inflammatory Bowel Diseases , Humans , Genome-Wide Association Study , Mendelian Randomization Analysis , Retrospective Studies , Inflammatory Bowel Diseases/genetics , Crohn Disease/genetics , Herpes Zoster/epidemiology , Herpes Zoster/genetics , Infectious Mononucleosis/geneticsABSTRACT
Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3-O-sulfotransferase 4 (HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.
Subject(s)
Herpes Zoster , Neuralgia, Postherpetic , Sulfotransferases/genetics , Genome-Wide Association Study , Herpes Zoster/genetics , Herpesvirus 3, Human/genetics , HumansABSTRACT
ABSTRACT: This brief definitive review of herpes zoster (HZ) will cover the current state of knowledge and questions that remain to be answered regarding HZ in general and HZ ophthalmicus in particular. A question-and-answer format will be used to address various important topics related to this common and serious disease. Questions to be addressed relate to common misconceptions, contagiousness of infection, unknowns regarding pathogenesis, rising incidence, risk factors and complications, relationship with temporal arteritis, vaccination, and current and future antiviral treatment. In addition, the importance of the Zoster Eye Disease Study to determine the efficacy of suppressive valacyclovir treatment in preventing complications of HZ ophthalmicus and the need to support enrollment will be discussed.
Subject(s)
Antiviral Agents/therapeutic use , Eye Infections, Viral/therapy , Herpes Zoster Ophthalmicus/therapy , Herpes Zoster Vaccine/therapeutic use , Herpes Zoster/genetics , RNA, Viral/analysis , Vaccination/methods , Eye Infections, Viral/epidemiology , Eye Infections, Viral/virology , Global Health , Herpes Zoster Ophthalmicus/epidemiology , Herpes Zoster Ophthalmicus/virology , Humans , IncidenceABSTRACT
OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta-analysis of genome-wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. METHODS: In an ethnicity/indication-specific, trans-ethnic, trans-population meta-analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long-term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. RESULTS: In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10-8 ), including a single-nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans-ethnic, trans-population meta-analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta-analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta-analysis hazard ratio 3.6 [95% confidence interval 2.40-5.44], P = 7.6 × 10-10 ; frequency of risk allele ~12% in East Asian subjects versus <0.2% in European subjects). CONCLUSION: Genetic analysis of tofacitinib-treated subjects with RA or PsO identified multiple loci associated with increased HZ risk. Prevalent variants near the immune-relevant genes CD83 and IL17RB in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib-treated subjects.
Subject(s)
Antigens, CD/genetics , Arthritis, Rheumatoid/drug therapy , Herpes Zoster/genetics , Immunoglobulins/genetics , Janus Kinase Inhibitors/adverse effects , Membrane Glycoproteins/genetics , Piperidines/adverse effects , Psoriasis/drug therapy , Pyrimidines/adverse effects , Receptors, Interleukin-17/genetics , Asian People/genetics , Genome-Wide Association Study , Herpes Zoster/chemically induced , Herpes Zoster/epidemiology , Humans , Logistic Models , Polymorphism, Single Nucleotide , Proportional Hazards Models , White People/genetics , CD83 AntigenABSTRACT
Background & objectives: Varicella zoster virus (VZV) strains are classified into six different clades based on the sequencing of its genome. Clades 4 and 5 are reported from India based on the single-nucleotide polymorphism (SNP). Till now, multiple clade circulations using partial sequences have been reported from India due to the lack of availability of the full VZV genome sequence. This study conducted a genome sequencing of VZV in India to identify circulating clade. Methods: Four clinical samples obtained from symptomatic patients tested positive for VZV by real-time PCR were used. These four samples were preferred to retrieve the genomic VZV sequence using the next-generation sequencing method. A reference-based assembly method was used to retrieve the genome of VZV, which was further analyzed. Results: At the least, 98 per cent of the whole-genome sequences were recovered from the four samples. The VZV sequences obtained in this study formed a separate monophyletic branch with clade 5, indicating it to be evolved from a distinct ancestor. The nucleotide-based analysis revealed 13 different SNP mutations and one multiple nucleotide variation in the VZV sequences when compared to one of the clade 5 genomes having accession number: DQ457052.1. Interpretation & conclusions: The present study described approximately 98 per cent of the genome sequence of VZV from India. The availability of these genomic sequences will lead to enrichment in the clinical genomic data set from India. The available data would help in the development of diagnostic methods along with evolutionary analysis. We hypothesize the existence of a new sub-clade that belongs to clade 5 and propose further experiments to confirm these results.
Subject(s)
Herpes Zoster , Herpesvirus 3, Human , Humans , Genome, Viral/genetics , Genotype , Herpes Zoster/epidemiology , Herpes Zoster/genetics , Herpesvirus 3, Human/genetics , Phylogeny , Polymorphism, Single NucleotideABSTRACT
Herpes zoster is associated with an increased dementia and neovascular macular degeneration risk and a decline in glycemic control in diabetes mellitus. Because amyloid is present and pathogenic in these diseases, we quantified amyloid, Aß40, Aß42, and amylin in 14 zoster and 10 control plasmas. Compared with controls, zoster plasma had significantly elevated amyloid that correlated with Aß42 and amylin levels and increased amyloid aggregation with addition of exogenous Aß42 or amylin. These results suggest that zoster plasma contains factor(s) that promotes aggregation of amyloidogenic peptides, potentially contributing to the toxic amyloid burden and explaining accelerated disease progression following zoster.
Subject(s)
Amyloid beta-Peptides/genetics , Herpes Zoster/blood , Herpesvirus 3, Human/pathogenicity , Islet Amyloid Polypeptide/genetics , Peptide Fragments/genetics , Protein Aggregation, Pathological/blood , Adult , Aged , Aged, 80 and over , Amyloid beta-Peptides/blood , Case-Control Studies , Female , Gene Expression , Herpes Zoster/genetics , Herpes Zoster/pathology , Herpesvirus 3, Human/growth & development , Host-Pathogen Interactions/genetics , Humans , Islet Amyloid Polypeptide/blood , Male , Middle Aged , Peptide Fragments/blood , Protein Aggregates , Protein Aggregation, Pathological/genetics , Protein Aggregation, Pathological/pathologyABSTRACT
Small noncoding RNAs (sncRNA), including microRNA (miR), are expressed by many viruses to provide an additional layer of gene expression regulation. Our work has shown that varicella-zoster virus (VZV; also called human herpesvirus 3 [HHV3]), the human alphaherpesvirus causing varicella and herpes zoster, expresses 24 virally encoded sncRNA (VZVsncRNA) in infected cells. Here, we demonstrate that several VZVsncRNA can modulate VZV growth, including four VZVsncRNA (VZVsncRNA10, -11, -12, and -13) that are antisense to VLT, a transcript made in lytic infections and associated with VZV latency. The influence on productive VZV growth and spread was assessed in epithelial cells transfected with locked nucleotide analog antagonists (LNAA). LNAA to the four VZVsncRNA antisense to VLT significantly reduced viral spread and progeny titers of infectious virus, suggesting that these sncRNA promoted lytic infection. The LNAA to VZVsncRNA12, encoded in the leader to ORF61, also significantly increased the levels of VLT transcripts. Conversely, overexpression of VZVsncRNA13 using adeno-associated virus consistently increased VZV spread and progeny titers. These results suggest that sncRNA antisense to VZV may regulate VZV growth, possibly by affecting VLT expression. Transfection of LNAA to VZVsncRNA14 and VZVsncRNA9 decreased and increased VZV growth, respectively, while LNAA to three other VZVsncRNA had no significant effects on replication. These data strongly support the conclusion that VZV replication is modulated by multiple virally encoded sncRNA, revealing an additional layer of complexity of VZV regulation of lytic infections. This may inform the development of novel anti-sncRNA-based therapies for treatment of VZV diseases.IMPORTANCE Varicella-zoster virus (VZV) causes herpes zoster, a major health issue in the aging and immunocompromised populations. Small noncoding RNAs (sncRNA) are recognized as important actors in modulating gene expression. This study extends our previous work and shows that four VZVsncRNA clustering in and near ORF61 and antisense to the latency-associated transcript of VZV can positively influence productive VZV infection. The ability of multiple exogenous small oligonucleotides targeting VZVsncRNA to inhibit VZV replication strengthens the possibility that they may inform development of novel treatments for painful herpes zoster.
Subject(s)
Herpesvirus 3, Human/genetics , RNA, Small Untranslated/genetics , RNA, Small Untranslated/metabolism , Chickenpox/genetics , Chickenpox/virology , Herpes Zoster/genetics , Herpes Zoster/virology , Herpesvirus 3, Human/growth & development , Humans , MicroRNAs/metabolism , Neurons/virology , Virus Latency , Virus ReplicationABSTRACT
Both the herpes zoster virus and suid herpesvirus type 1 (SuHV-1) belong to the Varicellovirus genus of the α-herpesviridae subfamily. They may cause opportunistic infections especially in patients with kidney diseases, varying from latent illness to overt lethality. Under these circumstances, impaired renal function is both the culprit for and victim of the infection. However, fulminant eruption of severe skin herpes zoster in lupus nephritis (LN) patients under prolonged immunosuppressive therapy is rare and even more rarely seen is the SuHV-1 encephalitis in human. Facing the evolution of these rare infections, we hence chose to review the clinical pathogenicity of these two viruses which were cognate in origin but distinct in virulence. As such, we began with the first of the two above viral diseases and proceeded with peculiar renal involvement, unique clinical symptoms and pertinent lethal risk. Of importance, LN was used to exemplify the reciprocally detrimental interactions between impaired renal function and suppressed immune response. Then in a manner similar to the gradient overlay, SuHV-1 encephalitis was discussed focusing on its neurotropic features, specific MRI findings and exclusive test of high throughput sequencing. Our report highlighted novel presentations of the Varicellovirus genus infection by providing a productive multidisciplinary communication with pointed disclosure of the renal involvement. It may therefore be of great medical relevance and educational value for clinicians, especially the unseasoned ones, to foresee and manage similar cases in susceptible patients.
Subject(s)
Herpes Zoster/epidemiology , Herpesvirus 1, Suid/pathogenicity , Infectious Encephalitis/epidemiology , Kidney Diseases/epidemiology , Animals , Herpes Zoster/complications , Herpes Zoster/genetics , Herpes Zoster/virology , Herpesviridae Infections/complications , Herpesviridae Infections/epidemiology , Herpesviridae Infections/genetics , Herpesviridae Infections/virology , Humans , Infectious Encephalitis/complications , Infectious Encephalitis/genetics , Infectious Encephalitis/virology , Kidney Diseases/complications , Kidney Diseases/genetics , Kidney Diseases/virology , Lupus Nephritis/complications , Lupus Nephritis/epidemiology , Lupus Nephritis/genetics , Lupus Nephritis/virology , Opportunistic Infections/complications , Opportunistic Infections/epidemiology , Opportunistic Infections/genetics , Opportunistic Infections/virology , Swine/virology , Varicellovirus/pathogenicitySubject(s)
Cation Transport Proteins/genetics , Epstein-Barr Virus Infections/diagnosis , Herpes Zoster/diagnosis , Herpesvirus 3, Human/physiology , Herpesvirus 4, Human/physiology , Mutation/genetics , X-Linked Combined Immunodeficiency Diseases/diagnosis , Adolescent , Child, Preschool , Epstein-Barr Virus Infections/genetics , Herpes Zoster/genetics , Humans , Magnesium Deficiency , Male , X-Linked Combined Immunodeficiency Diseases/geneticsABSTRACT
BACKGROUND: Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus. METHODS: Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed. RESULTS: Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised. CONCLUSIONS: We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.
Subject(s)
Herpes Zoster Ophthalmicus/virology , Herpesvirus 3, Human/pathogenicity , Mutation/genetics , Toll-Like Receptor 3/genetics , Adult , Encephalitis, Herpes Simplex/genetics , Encephalitis, Herpes Simplex/virology , Female , Fibroblasts/virology , Herpes Zoster/genetics , Herpes Zoster/virology , Herpes Zoster Ophthalmicus/genetics , Humans , Immunocompromised Host/geneticsABSTRACT
Varicella zoster virus (VZV) is a skin-tropic virus that infects epidermal keratinocytes and causes chickenpox. Although common, VZV infection can be life-threatening, particularly in the immunocompromized. Therefore, understanding VZV-keratinocyte interactions is important to find new treatments beyond vaccination and antiviral drugs. In VZV-infected skin, kallikrein 6 and the ubiquitin ligase MDM2 are upregulated concomitant with keratin 10 (KRT10) downregulation. MDM2 binds to KRT10, targeting it for degradation via the ubiquitin-proteasome pathway. Preventing KRT10 degradation reduced VZV propagation in culture and prevented epidermal disruption in skin explants. KRT10 knockdown induced expression of NR4A1 and enhanced viral propagation in culture. NR4A1 knockdown prevented viral propagation in culture, reduced LC3 levels, and increased LAMP2 expression. We therefore describe a drug-able pathway whereby MDM2 ubiquitinates and degrades KRT10, increasing NR4A1 expression and allowing VZV replication and propagation.
Subject(s)
Gene Expression Regulation , Herpes Zoster/genetics , Herpes Zoster/metabolism , Herpesvirus 3, Human/physiology , Keratin-10/genetics , Keratinocytes/pathology , RNA/genetics , Virus Replication , Herpes Zoster/virology , Humans , Keratin-10/biosynthesis , Keratinocytes/metabolism , Keratinocytes/virologyABSTRACT
The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).
Subject(s)
Electronic Health Records , Genetic Predisposition to Disease , Genome-Wide Association Study , Herpes Zoster/genetics , Algorithms , Black People/genetics , Chromosomes, Human/genetics , Female , Haplotypes/genetics , Homozygote , Humans , Male , Phenotype , Polymorphism, Single Nucleotide/genetics , Principal Component Analysis , White People/geneticsABSTRACT
In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity. Here we describe the roles of POL III in housekeeping and immune surveillance during VZV infection. We present the latest knowledge on the role of POL III in VZV infection and discuss outstanding questions related to the role of POL III in VZV immunity, and how this insight can be translated into clinical medicine.
Subject(s)
Chickenpox/genetics , Encephalitis, Varicella Zoster/genetics , Herpes Zoster/genetics , Host-Pathogen Interactions , RNA Polymerase III/genetics , Virus Activation , Adult , Chickenpox/immunology , Chickenpox/pathology , Chickenpox/virology , DEAD Box Protein 58/genetics , DEAD Box Protein 58/immunology , DNA, Viral/genetics , DNA, Viral/immunology , Encephalitis, Varicella Zoster/immunology , Encephalitis, Varicella Zoster/pathology , Encephalitis, Varicella Zoster/virology , Gene Expression Regulation , Genetic Predisposition to Disease , Herpes Zoster/immunology , Herpes Zoster/pathology , Herpes Zoster/virology , Herpesvirus 3, Human/genetics , Herpesvirus 3, Human/immunology , Humans , Immunity, Innate , Immunologic Surveillance , Interferons/genetics , Interferons/immunology , Protein Subunits/genetics , Protein Subunits/immunology , RNA Polymerase III/immunology , Receptors, ImmunologicABSTRACT
Objective: To analyze the genetic characterization of glycoprotein M(gM.),glycoprotein L(gL) of varicella zoster virus. Methods: According to the program of "Ministry of Science and Technology of China" , Based on the 12 suspected VZV patients monitored in Beijing (1 case), Shanghai (5 cases), Jilin (2 cases), Qinghai (1 case), Guangdong (2 case) and Sichuan (case) in 2007-2015. A total of 12 Vesicle fluid and throat swab samples were collected. Positive samples were identified by Agarose gel electrophoresis and two glycoprotein genes were amplified by polymerase chain reaction (PCR). Nucleotide sequences were determined and analyzed by PCR amplification of VZV positive specimens V-OKA-BK of the domestic varicella attenuated live vaccine and the Varilrix-1 of the imported attenuated live vaccine. Nucleotide sequences of VZV positive specimens, vaccine strains (V-OKA-BK, varilrix-1) and GenBank foreign wild strains (41 strains), parent strains (P-oka), vaccine strains (V-oka, Varilrix, Varivax) were compared using BioEdit and MEGA 5.0. Results: 12 specimens were VZV positive. Compared with the vaccine strains and the parent strains, the GM gene of 1 positive specimen had radical mutation at 86686 sites, which resulted in amino acid mutation, 5 positive specimens had base mutation at 87844 sites, and 30 strains of foreign wild strains had the same variation at 87 844 sites. 1 positive specimens of gL gene in 101245 sites had base mutation, and led to amino acid mutation, 6 positive specimens at 101624, 101625, 101626 sites had base of loss and the foreign wild strains in these 3 sites had the same variation. Compared with the vaccine strains, the nucleotide and amino acid homology of gM of 12 VZV positive specimens were 99.2%-100% and 98.2%-100%, respectively, and gL of those were 99.3%-100% and 98.6%-100%, respectively. Compared with 41 strains of foreign wild strains, homology of gM's nucleotides and amino acid were 99.3%-100% and 98.5%-100%, respectively; 99.1%-100% and 98.6%-100% for gL. The results of phylogenetic analysis showed that 7 VZV positive samples were on the same branch with 4 vaccine strains and p-oka strain. Based on gL, 12 VZV positive samples were on the same branch as the vaccine strains and p-oka strain. Conclusion: This study demonstrates that the genes of gM, gL are highly conserved and remain stable immunogen, which may be involved in the attenuation of VZV and need to be further researched.
Subject(s)
Genes, Viral , Herpes Zoster/genetics , Herpesvirus 3, Human/genetics , Phylogeny , Base Sequence , Beijing , Chickenpox , Chickenpox Vaccine , China , Humans , Immunogenetic Phenomena , Mutation , Polymerase Chain Reaction , Vaccines, AttenuatedABSTRACT
The study included 50 adult patients with shingles by which analyzed the clinical course of the disease depending on the gene polymorphism of interleukin-10 (rs 1800896) and toll-like receptor 2 (rs 5743708). According to the results of our study, it was established that genotype AA of gene Toll-like receptor 2 was associated with a high risk of Varicella-Zoster virus reactivation and manifestation of herpes zoster, moderate course. Analysis of the IL-10 gene polymorphism showed that genotype TT was associated with a risk of the development severe complicated course of shingles. The genotype CC of gene IL-10 caused to formation of recurrence course of the disease, and also significantly more frequently registered in patients with disseminated form of herpes zoster compared with patients with localized and generalized forms of the disease (χ2=11,94, Ñ=0.0003). Subject to the formation of localized form in carriers of genotype CC more often was occurred damage paravertebral ganglia (p=0.01).
Subject(s)
Herpes Zoster/genetics , Interleukin-10/genetics , Polymorphism, Single Nucleotide , Toll-Like Receptor 2/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Gene Frequency , Genotype , Herpes Zoster/immunology , Herpes Zoster/virology , Humans , Male , Middle Aged , Recurrence , Severity of Illness Index , Virus Activation/immunologyABSTRACT
BACKGROUND: Studies have investigated a possible association between family history of HZ and the occurrence of HZ. However, the results were inconclusive and susceptible to bias. We evaluated this association in an elderly population. METHODS: The matched case-control study conducted at Kaiser Permanente Southern California in 2012-2015 included 656 incident HZ patients ≥60 whose skin lesion tested positive for varicella zoster virus by polymerase chain reaction. Half of the HZ patients were vaccinated with zoster vaccine as achieved by stratified sampling. The controls were randomly selected and 1:1 matched to the cases on sex, age (±1year), and zoster vaccination (±3 months of the case's vaccination date). Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Having any blood relative with a history of HZ was associated with a slightly increased risk of HZ (adjusted OR=1.37, 95% CI 1.05-1.79). The adjusted OR associated with having one and two categories of first-degree blood relatives with a history of HZ was 1.30 (95% CI: 0.97-1.73) and 2.53 (95% CI: 1.17-5.44), respectively. CONCLUSIONS: Our results suggested a weak association between the development of HZ and a positive family history of HZ among the elderly population.
Subject(s)
Herpes Zoster/genetics , Herpesvirus 3, Human , Aged , Aged, 80 and over , California , Case-Control Studies , Family Health , Female , Herpes Zoster/epidemiology , Herpes Zoster Vaccine , Herpesvirus 3, Human/immunology , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Risk FactorsABSTRACT
Around 30% of individuals will develop herpes zoster (HZ), caused by the varicella zoster virus (VZV), during their life. While several risk factors for HZ, such as immunosuppressive therapy, are well known, the genetic and molecular components that determine the risk of otherwise healthy individuals to develop HZ are still poorly understood. We created a computational model for the Human Leukocyte Antigen (HLA-A, -B, and -C) presentation capacity of peptides derived from the VZV Immediate Early 62 (IE62) protein. This model could then be applied to a HZ cohort with known HLA molecules. We found that HLA-A molecules with poor VZV IE62 presentation capabilities were more common in a cohort of 50 individuals with a history of HZ compared to a nationwide control group, which equated to a HZ risk increase of 60%. This tendency was most pronounced for cases of HZ at a young age, where other risk factors are less prevalent. These findings provide new molecular insights into the development of HZ and reveal a genetic predisposition in those individuals most at risk to develop HZ.
Subject(s)
HLA-A Antigens/immunology , Herpes Zoster/immunology , Herpesvirus 3, Human/immunology , Immediate-Early Proteins/immunology , Trans-Activators/immunology , Viral Envelope Proteins/immunology , Adult , Aged , Belgium/epidemiology , Chickenpox/immunology , Chickenpox/virology , Female , Genetic Predisposition to Disease , Herpes Zoster/epidemiology , Herpes Zoster/genetics , Humans , Immediate-Early Proteins/genetics , Male , Middle Aged , Models, Immunological , Risk Factors , Trans-Activators/genetics , Viral Envelope Proteins/geneticsABSTRACT
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.
Subject(s)
HLA Antigens/genetics , Infections/genetics , White People/genetics , Candidiasis, Vulvovaginal/genetics , Case-Control Studies , Chickenpox/genetics , Chronic Disease , Common Cold/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Hepatitis A/genetics , Hepatitis B/genetics , Herpes Labialis/genetics , Herpes Zoster/genetics , Humans , Infectious Mononucleosis/genetics , Male , Measles/genetics , Meningitis, Bacterial/genetics , Middle Ear Ventilation , Mumps/genetics , Otitis Media/genetics , Otitis Media/surgery , Pharyngitis/genetics , Pneumonia/genetics , Rheumatic Fever/genetics , Rubella/genetics , Scarlet Fever/genetics , Sinusitis/genetics , Streptococcal Infections/genetics , Tonsillectomy , Tonsillitis/genetics , Tonsillitis/surgery , Tuberculin Test , Tuberculosis/diagnosis , Tuberculosis/genetics , Urinary Tract Infections/genetics , Warts/geneticsABSTRACT
Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.