RESUMEN
Postherpetic neuralgia (PHN) is a common, severe, and hard-to-treat chronic pain condition in clinics. Although PHN is developed from herpes zoster (HZ), the developing mechanism is unknown. A previous study investigated blood metabolomic and proteomic profiling in patients with PHN and HZ. The current study aims to explore the blood transcriptomic signature of PHN compared to HZ patients. Whole blood from eight PHN and 15 HZ patients was used for RNA-Seq analysis. There were 82 and 1,788 genes detected specifically in the PHN and HZ groups, respectively. PHN-specific genes are involved in viral infection, lipid and carbohydrate metabolism, and immune response. For genes coexpressed in PHN and HZ patients, there were 407 differential expression genes (DEGs), including 205 upregulated (UP DEGs) and 202 downregulated (DOWN DEGs) in PHN compared to HZ groups. DEGs are involved in viral infection, type I interferon (IFN), and hemoglobin and oxygen carrier activity. UP DEGs are associated with regulatory T cells (Tregs), activated NK cells, and neutrophils, while DOWN DEGs are associated with Tregs, resting NK cells, and monocytes. The results suggest that the metabolism of lipid, glycan, and nucleotides, type I IFN signaling, and altered neutrophil activation are associated with and might contribute to the development of PHN in HZ. It is also suggested that persistent or altered activation of nonspecific immunity may contribute to the development of PHN from HZ.
Asunto(s)
Perfilación de la Expresión Génica , Herpes Zóster , Neuralgia Posherpética , Transcriptoma , Humanos , Herpes Zóster/sangre , Herpes Zóster/virología , Neuralgia Posherpética/sangre , Masculino , Femenino , Anciano , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Herpesvirus Humano 3/genética , Células Asesinas Naturales/inmunología , Metabolismo de los Lípidos/genéticaRESUMEN
The impact of viral keratitis (VK) on individuals and society is notable. Early diagnosis and treatment are crucial in managing viral keratitis effectively. Timely intervention with antiviral medications and supportive care can help mitigate the severity of the infection and improve visual outcomes. We examined the prevalence of varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), adenovirus (AdV) and herpes simplex virus type 2 (HSV-2) in patients suspected for ocular infections. Patients included in the study exhibited various clinical manifestations indicative of ocular pathology, such as infectious keratitis, corneal scar, endogenous endophthalmitis, panuveitis, endothelitis, stromal edema, and other relevant conditions. Four different types of tear fluid, corneal samples epithelium, aqueous humor and vitreous humor were taken. After genome extraction, multiplex real-time PCR was used for diagnosis of viruses. 48 (29.6%) out of the total of 162 (100%) eye specimen were positive. The dominant prevalence was VZV (12.3%) and HSV-1 (11.7%) followed by AdV (4.9%) and HSV-2 (0.6%). There were 4 (8.3%) coinfections within the samples (HSV-1 and VZV). Aqueous humor samples demonstrated superior virus detection ability and our only HSV-2 positive sample was from aqueous humor. The utilization of multiplex real-time PCR assays in differential diagnosis of VK holds promise for expeditious diagnoses while also preventing unwarranted antibiotic prescriptions. Moreover, the aqueous humor appears to be a more sensitive site for detecting viral keratitis.
Asunto(s)
Humor Acuoso , Reacción en Cadena de la Polimerasa Multiplex , Humanos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Humor Acuoso/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/aislamiento & purificación , Anciano , Infecciones Virales del Ojo/virología , Infecciones Virales del Ojo/diagnóstico , Infecciones Virales del Ojo/epidemiología , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/aislamiento & purificación , Adolescente , Adulto Joven , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/aislamiento & purificación , Virosis/diagnóstico , Virosis/virología , Virosis/epidemiología , Niño , Queratitis/virología , Queratitis/diagnóstico , Queratitis/epidemiología , Lágrimas/virologíaRESUMEN
mRNA platform holds promise for next-generation Varicella-zoster Virus (VZV) vaccine development due to its high potency at inducing strong T-cell response. Built upon the design of our 1st-generation VZV mRNA vaccine that encodes for full-length gE antigen, in this study we reported on a novel combinatorial strategy to further optimize the gE-encoding mRNA sequence through signal peptide replacement, C-terminal modification, and insertion of mRNA-stabilizing motif, which collectively contributed to significantly improved vaccine immunogenicity. In adult mice, aged mice, and immunocompromised mice, this optimized VZV mRNA vaccine showed strong superiority in multiple aspects including the induction of gE-specific antibodies, specific memory B-cell response, as well as Th1-type T-cell response.
Asunto(s)
Anticuerpos Antivirales , Herpesvirus Humano 3 , Proteínas del Envoltorio Viral , Animales , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/genética , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/genética , Ratones , Anticuerpos Antivirales/inmunología , Humanos , Vacunas de ARNm , ARN Mensajero/genética , ARN Mensajero/inmunología , Femenino , Desarrollo de Vacunas , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Inmunogenicidad Vacunal , Vacuna contra la Varicela/inmunología , Vacuna contra la Varicela/administración & dosificación , Vacuna contra la Varicela/genética , Linfocitos B/inmunología , Ratones Endogámicos BALB C , Células TH1/inmunologíaAsunto(s)
Varicela , Inmunización Secundaria , Humanos , Varicela/virología , Resultado Fatal , Herpesvirus Humano 3/aislamiento & purificación , Herpesvirus Humano 3/genética , Vacuna contra la Varicela/efectos adversos , Vacuna contra la Varicela/administración & dosificación , Vacuna contra la Varicela/inmunología , Masculino , Inmunocompetencia , Femenino , PreescolarRESUMEN
This study investigates the role of circular RNAs (circRNAs) in the context of Varicella-Zoster Virus (VZV) lytic infection. We employ two sequencing technologies, short-read sequencing and long-read sequencing, following RNase R treatment on VZV-infected neuroblastoma cells to identify and characterize both cellular and viral circRNAs. Our large scanning analysis identifies and subsequent experiments confirm 200 VZV circRNAs. Moreover, we discover numerous VZV latency-associated transcripts (VLTs)-like circRNAs (circVLTslytic), which contain multiple exons and different isoforms within the same back-splicing breakpoint. To understand the functional significance of these circVLTslytic, we utilize the Bacteria Artificial Chromosome system to disrupt the expression of viral circRNAs in genomic DNA location. We reveal that the sequence flanking circVLTs' 5' splice donor plays a pivotal role as a cis-acting element in the formation of circVLTslytic. The circVLTslytic is dispensable for VZV replication, but the mutation downstream of circVLTslytic exon 5 leads to increased acyclovir sensitivity in VZV infection models. This suggests that circVLTslytic may have a role in modulating the sensitivity to antiviral treatment. The findings shed new insight into the regulation of cellular and viral transcription during VZV lytic infection, emphasizing the intricate interplay between circRNAs and viral processes.
Asunto(s)
Herpesvirus Humano 3 , ARN Circular , ARN Viral , Replicación Viral , ARN Circular/genética , ARN Circular/metabolismo , Herpesvirus Humano 3/genética , Humanos , ARN Viral/genética , ARN Viral/metabolismo , Replicación Viral/genética , Línea Celular Tumoral , Latencia del Virus/genética , Infección por el Virus de la Varicela-Zóster/virología , Aciclovir/farmacología , Aciclovir/uso terapéutico , Exones/genéticaRESUMEN
Syphilis, caused by Treponema pallidum subsp. pallidum (TPA), is becoming a significant public health concern, with rising incidence in Manitoba exceeding the national average. The province has also seen a demographic shift leading to women representing 51.9% of cases in 2021, leading to the re-emergence of congenital syphilis. Given the similarities in lesion appearance between TPA and other pathogens such as herpesviruses, accurate diagnosis is crucial for effective management and prevention. In order to address the potential for missed TPA cases, we conducted a quality assurance study from June 2021 to March 2023, screening over 5,000 mucocutaneous lesion swabs for TPA, initially submitted for herpes simplex virus (HSV) and varicella zoster virus (VZV) testing. Positivity rates were 13% for HSV1, 13% for HSV2, 6.7% for VZV, and 6.6% for TPA. Turnaround times (TAT) for TPA testing, as a send-out to the reference laboratory, averaged 17.8 days. Of the TPA-positive specimens, 36% did not have a corresponding TPA PCR test ordered, and 19% did not have accompanying syphilis serology within 30 days of collection. Creation of a multiplex lesion panel identified high sensitivity and specificity for HSV1, HSV2, VZV, and TPA, with robust reproducibility across multiple runs. Incorporation of TPA into a lesion panel improved the TAT to 4 days. Our findings emphasize the need for improved testing strategies to combat the syphilis epidemic and enhance public health outcomes.IMPORTANCESyphilis resurgence has become a significant global public health concern. In particular, the Canadian Prairies have been struggling with high incidence since 2016, exceeding the national Canadian average. We undertook a quality assurance study that highlighted significant gaps in diagnosis of acute syphilis, which led to the development of a highly sensitive and specific multiplex lesion assay for the dual detection of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella zoster virus (VZV), and syphilis.
Asunto(s)
Herpesvirus Humano 1 , Herpesvirus Humano 2 , Herpesvirus Humano 3 , Sífilis , Treponema pallidum , Humanos , Manitoba/epidemiología , Sífilis/diagnóstico , Sífilis/epidemiología , Femenino , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 1/genética , Treponema pallidum/aislamiento & purificación , Herpesvirus Humano 3/aislamiento & purificación , Herpesvirus Humano 3/genética , Herpesvirus Humano 2/aislamiento & purificación , Herpesvirus Humano 2/genética , Masculino , Herpes Simple/diagnóstico , Herpes Simple/epidemiología , Adulto , Infección por el Virus de la Varicela-Zóster/diagnóstico , Infección por el Virus de la Varicela-Zóster/epidemiología , Sensibilidad y EspecificidadRESUMEN
The monkeypox virus (MPXV) outbreak, primarily endemic to Africa, has spread globally, with Brazil reporting the second-highest number of cases. The emergence of MPXV in non-endemic areas has raised concerns, particularly due to the co-circulation of other exanthematous viruses such as varicella-zoster virus (VZV) and molluscum contagiosum virus (MOCV). To perform an accurate differential diagnosis of MPXV during the ongoing outbreak in Minas Gerais, Brazil, a 5PLEX qPCR assay targeting orthopoxviruses (OPV), VZV, and MOCV was used to retrospectively analyze all clinical samples that tested negative for MPXV in the initial screening conducted at Funed. In summary, our study analyzed 1,175 clinical samples received from patients suspected of MPXV infection and found a positivity rate of 33.8% (397 samples) for MPXV using the non-variola qPCR assay. Testing the 778 MPXV-negative clinical samples using the 5PLEX qPCR assay revealed that 174 clinical samples (22.36%) tested positive for VZV. MOCV DNA was detected in 13 and other OPV in 3 clinical samples. The sequencing of randomly selected amplified clinical samples confirmed the initial molecular diagnosis. Analysis of patient profiles revealed a significant difference in the median age between groups testing positive for MPXV and VZV and a male predominance in MPXV cases. The geographic distribution of positive cases was concentrated in the most populous mesoregions of Minas Gerais state. This study highlights the challenges posed by emerging infectious diseases. It emphasizes the importance of epidemiological surveillance and accurate diagnosis in enabling timely responses for public health policies and appropriate medical care. IMPORTANCE: Brazil ranks second in the number of cases during the global monkeypox epidemic. The study, conducted in Minas Gerais, the second most populous state in Brazil with over 20 million inhabitants, utilized differential diagnostics, revealing a significant number of positive cases for other exanthematous viruses and emphasizing the need for accurate diagnoses. During the study, we were able to assess the co-circulation of other viruses alongside monkeypox, including varicella-zoster virus, molluscum contagiosum virus, and other orthopoxviruses. The significance of the research is underscored by the concentration of positive cases in populous areas, highlighting the challenges posed by emerging infectious diseases. This demographic context further amplifies the importance of the research in guiding public health policies and medical interventions, given the substantial population at risk. The study not only addresses a global concern but also holds critical implications for a state with such a large population and geographic expanse within Brazil. Overall, the study emphasizes the pivotal role of surveillance and precise diagnosis in guiding effective public health responses and ensuring appropriate medical interventions.
Asunto(s)
Brotes de Enfermedades , Humanos , Brasil/epidemiología , Estudios Retrospectivos , Masculino , Femenino , Adulto , Diagnóstico Diferencial , Niño , Adolescente , Mpox/diagnóstico , Mpox/epidemiología , Mpox/virología , Adulto Joven , Preescolar , Persona de Mediana Edad , Monkeypox virus/genética , Monkeypox virus/aislamiento & purificación , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/aislamiento & purificación , Lactante , Anciano , Exantema/virología , Exantema/epidemiología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
In this study, we investigated the role of serum/glucocorticoid-regulated kinase 1 (SGK1) in varicella-zoster virus (VZV) replication. VZV DNA replication and plaque formation were inhibited by SGK1 knockout and treatment with an SGK1 inhibitor. Furthermore, SGK1 inhibition suppressed the increase in cyclin B1 expression induced by VZV infection. These results suggest that VZV infection induces SGK1 activation, which is required for efficient viral proliferation through the expression of cyclin B1. This is the first study to report that SGK1 is involved in the VZV life cycle.
Asunto(s)
Ciclina B1 , Herpesvirus Humano 3 , Proteínas Inmediatas-Precoces , Proteínas Serina-Treonina Quinasas , Replicación Viral , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Humanos , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Ciclina B1/metabolismo , Ciclina B1/genética , Línea Celular , Replicación del ADNRESUMEN
OBJECTIVES: Encephalitis is a severe neurological syndrome for which herpesvirus and enteroviruses are the most common etiological agents. Arboviruses, a wildly diverse group of pathogens, are also critical epidemiological agents associated with encephalitis. In Brazil, little is known about the causative agents of encephalitis. METHODS: We conducted a hospital surveillance for encephalitis between 2020 and 2022. Molecular (RT-PCR and qPCR) and serological (virus-specific IgM and viral antigens) techniques were performed in cerebrospinal fluid and serum samples obtained from study participants. RESULTS: In the 43 participants evaluated, the etiologic agent or the presence of IgM was detected in 16 (37.2%). Nine (20.9%) cases were positive for chikungunya virus (CHIKV), three (7.0%) for dengue virus, two (4.7%) for human adenovirus, one (2.3%) for varicella-zoster virus, and one (2.3%) for enterovirus. Whole-genome sequencing revealed that the CHIKV identified belongs to the East/Central/South African lineage. CONCLUSION: Herein, CHIKV is a common pathogen identified in encephalitis cases. Our results reinforce previous evidence that chikungunya represents a significant cause of encephalitis during CHIKV outbreaks and epidemics and add to existing information on the epidemiology of encephalitis in Brazil.
Asunto(s)
Fiebre Chikungunya , Virus Chikungunya , Humanos , Brasil/epidemiología , Virus Chikungunya/genética , Virus Chikungunya/aislamiento & purificación , Masculino , Femenino , Fiebre Chikungunya/epidemiología , Fiebre Chikungunya/virología , Fiebre Chikungunya/diagnóstico , Fiebre Chikungunya/sangre , Adulto , Adolescente , Niño , Adulto Joven , Persona de Mediana Edad , Preescolar , Anticuerpos Antivirales/sangre , Encefalitis Viral/epidemiología , Encefalitis Viral/virología , Encefalitis Viral/diagnóstico , Inmunoglobulina M/sangre , Anciano , Virus del Dengue/genética , Virus del Dengue/aislamiento & purificación , Lactante , Filogenia , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/aislamiento & purificación , Enterovirus/aislamiento & purificación , Enterovirus/genética , Secuenciación Completa del GenomaRESUMEN
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.
Asunto(s)
Herpesvirus Humano 3 , Transducción de Señal , Piel , Infección por el Virus de la Varicela-Zóster , Herpesvirus Humano 3/genética , Piel/patología , Piel/virología , Piel/inmunología , Animales , Infección por el Virus de la Varicela-Zóster/virología , Infección por el Virus de la Varicela-Zóster/inmunología , Infección por el Virus de la Varicela-Zóster/genética , Infección por el Virus de la Varicela-Zóster/patología , Humanos , Ratones , Células Dendríticas/inmunología , Herpes Zóster/virología , Herpes Zóster/patología , Herpes Zóster/genética , Herpes Zóster/inmunología , Transcriptoma , Modelos Animales de Enfermedad , Antígenos Virales/inmunología , Antígenos Virales/genética , FN-kappa B/metabolismo , FN-kappa B/genéticaRESUMEN
Mpox is a zoonotic disease historically reported in Africa. Since 2003, limited outbreaks have occurred outside Africa. In 2022, the global spread of cases with sustained interhuman transmission and unusual disease features raised public health concerns. We explore the mpox outbreak in Rio de Janeiro (RJ) state, Brazil, in an observational study of mpox-suspected cases from June to December 2022. Data collection relied on a public healthcare notification form. Diagnosis was determined by MPXV-PCR. In 46 confirmed cases, anti-OPXV IgG was determined by ELISA, and seven MPXV genomes were sequenced. A total of 3095 cases were included, 816 (26.3%) with positive MPXV-PCR results. Most positive cases were men in their 30 s and MSM. A total of 285 (34.9%) MPXV-PCR+ patients live with HIV. Eight were coinfected with varicella-zoster virus. Anogenital lesions and adenomegaly were associated with the diagnosis of mpox. Females and individuals under 18 represented 9.4% and 5.4% of all confirmed cases, respectively, showing higher PCR cycle threshold (Ct) values and fewer anogenital lesions compared to adult men. Anti-OPXV IgG was detected in 29/46 (63.0%) patients. All analyzed sequences belonged to clade IIb. In RJ state, mpox presented a diverse clinical picture, represented mainly by mild cases with low complication rates and prominent genital involvement. The incidence in females and children was higher than usually reported. The observation of a bimodal distribution of Ct values, with few positive results, may suggest the need to review the diagnostic criteria in these groups.
Asunto(s)
Brotes de Enfermedades , Humanos , Brasil/epidemiología , Masculino , Femenino , Adulto , Adulto Joven , Adolescente , Persona de Mediana Edad , Animales , Zoonosis/epidemiología , Zoonosis/virología , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/aislamiento & purificación , Niño , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Anticuerpos Antivirales/sangre , Anciano , Inmunoglobulina G/sangreRESUMEN
Although all herpesviruses utilize a highly conserved replication machinery to amplify their viral genomes, different members may have unique strategies to modulate the assembly of their replication components. Herein, we characterize the subcellular localization of seven essential replication proteins of varicella-zoster virus (VZV) and show that several viral replication enzymes such as the DNA polymerase subunit ORF28, when expressed alone, are localized in the cytoplasm. The nuclear import of ORF28 can be mediated by the viral DNA polymerase processivity factor ORF16. Besides, ORF16 could markedly enhance the protein abundance of ORF28. Noteworthily, an ORF16 mutant that is defective in nuclear transport still retained the ability to enhance ORF28 abundance. The low abundance of ORF28 in transfected cells was due to its rapid degradation mediated by the ubiquitin-proteasome system. We additionally reveal that radicicol, an inhibitor of the chaperone Hsp90, could disrupt the interaction between ORF16 and ORF28, thereby affecting the nuclear entry and protein abundance of ORF28. Collectively, our findings imply that the cytoplasmic retention and rapid degradation of ORF28 may be a key regulatory mechanism for VZV to prevent untimely viral DNA replication, and suggest that Hsp90 is required for the interaction between ORF16 and ORF28.
Asunto(s)
Transporte Activo de Núcleo Celular , ADN Polimerasa Dirigida por ADN , Herpesvirus Humano 3 , Proteínas Virales , Replicación Viral , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/metabolismo , Humanos , Proteínas Virales/metabolismo , Proteínas Virales/genética , ADN Polimerasa Dirigida por ADN/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Núcleo Celular/metabolismo , Núcleo Celular/virología , Citoplasma/metabolismo , Citoplasma/virología , Línea Celular , Replicación del ADNRESUMEN
Human herpes virus is a family of DNA viruses that includes herpes simplex virus (HSV) and varicella zoster virus (VZV). HSV-1 and HSV-2 are fairly common and result in oral and genital lesions. Recurrent infections of herpes include lesions on the lips resulting in pain and possibly societal stigma, making adequate treatment of these conditions crucial. VZV is the cause of chicken pox and shingles. Acyclovir and other nucleoside analogues have been the gold standard of treatment for HSV and VZV, but newer, more effective treatments are being developed, which is beneficial regarding the issue of resistance to standard antivirals. Human papillomavirus (HPV) is also a DNA virus with different subtypes that result in four common oral benign lesions. The significance and treatments of HSV, VZV, and HPV are discussed, along with certain developing treatments of herpes labialis (HSV).
Asunto(s)
Herpes Zóster , Herpesvirus Humano 1 , Infecciones por Papillomavirus , Humanos , Herpesvirus Humano 3/genética , Virus del Papiloma Humano , Infecciones por Papillomavirus/terapia , Herpesvirus Humano 1/genéticaRESUMEN
BACKGROUND: Psychiatric disorders, such as schizophrenia (SCZ), major depressive (MDD), and bipolar disorder (BD) have a profound impact on millions of individuals worldwide. The critical step toward developing effective preventive and treatment strategies lies in comprehending the causal mechanisms behind these diseases and identifying modifiable risk factors associated with them. METHODS: In this study, we conducted a 2-sample Mendelian randomization analysis to explore the potential links between chickenpox(varicella-zoster virus infection) and three major psychiatric disorders(SCZ, MDD, BD). RESULTS: In our MR study, among the three major psychiatric disorders, chickenpox was shown to be causally related to BD, indicating that infection with chickenpox may increase the risk of developing BD (IVW: OR = 1.064, 95% CI =1.025-1.104, P=0.001; RAPS: OR=1.066, 95% CI=1.024-1.110, P=0.002), while there was no causal relationship between SCZ and MDD. Similar estimated causal effects were observed consistently across the various MR models. The robustness of the identified causal relationship between chickenpox and BD holds true regardless of the statistical methods employed, as confirmed by extensive sensitivity analyses that address violations in model assumptions. The MR-Egger regression test failed to reveal any signs of directional pleiotropy (intercept = -0.042, standard error (SE) = 0.029, p = 0.236). Similarly, the MR-PRESSO analysis revealed no evidence of directional pleiotropy or outliers among the chickenpox-related instrumental variables (global test p = 0.653). Furthermore, a leave-one-out sensitivity analysis yielded consistent results, further underscoring the credibility and stability of the causal relationship. CONCLUSIONS: Our findings provide compelling evidence of a causal effect of chickenpox on the risk of BD. To gain a more comprehensive understanding of this association and its underlying mechanisms, additional research is needed. Such investigations are pivotal in identifying effective interventions for promoting BD prevention.
Asunto(s)
Varicela , Trastorno Depresivo Mayor , Trastornos Mentales , Humanos , Herpesvirus Humano 3/genética , Varicela/epidemiología , Trastorno Depresivo Mayor/genética , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma CompletoRESUMEN
Herpesviruses replicate by cleaving concatemeric dsDNA into single genomic units that are packaged through an oligomeric portal present in preformed procapsids. In contrast to what is known about phage portal proteins, details concerning herpesvirus portal structure and function are not as well understood. A panel of 65 Varicella-Zoster virus (VZV) recombinant portal proteins with five amino acid in-frame insertions were generated by random transposon mutagenesis of the VZV portal gene, ORF54. Subsequently, 65 VZVLUC recombinant viruses (TNs) were generated via recombineering. Insertions were mapped to predicted portal domains (clip, wing, stem, wall, crown, and ß-hairpin tunnel-loop) and recombinant viruses were characterized for plaque morphology, replication kinetics, pORF54 expression, and classified based on replication in non-complementing (ARPE19) or complementing (ARPE54C50) cell lines. The N- and C-termini were tolerant to insertion mutagenesis, as were certain clip sub-domains. The majority of mutants mapping to the wing, wall, ß-hairpin tunnel loop, and stem domains were lethal. Elimination of the predicted ORF54 start codon revealed that the first 40 amino acids of the N-terminus were not required for viral replication. Stop codon insertions in the C-terminus showed that the last 100 amino acids were not required for viral replication. Lastly, a putative protease cleavage site was identified in the C-terminus of pORF54. Cleavage was likely orchestrated by a viral protease; however, processing was not required for DNA encapsidation and viral replication. The panel of recombinants should prove valuable in future studies to dissect mammalian portal structure and function.IMPORTANCEThough nucleoside analogs and a live-attenuated vaccine are currently available to treat some human herpesvirus family members, alternate methods of combating herpesvirus infection could include blocking viral replication at the DNA encapsidation stage. The approval of Letermovir provided proof of concept regarding the use of encapsidation inhibitors to treat herpesvirus infections in the clinic. We propose that small-molecule compounds could be employed to interrupt portal oligomerization, assembly into the capsid vertex, or affect portal function/dynamics. Targeting portal at any of these steps would result in disruption of viral DNA packaging and a decrease or absence of mature infectious herpesvirus particles. The oligomeric portals of herpesviruses are structurally conserved, and therefore, it may be possible to find a single compound capable of targeting portals from one or more of the herpesvirus subfamilies. Drug candidates from such a series would be effective against viruses resistant to the currently available antivirals.
Asunto(s)
Infecciones por Herpesviridae , Herpesvirus Humano 3 , Animales , Humanos , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/metabolismo , Mutagénesis , Replicación Viral , Infecciones por Herpesviridae/genética , ADN/metabolismo , Aminoácidos/genética , Mamíferos/genéticaRESUMEN
OBJECTIVE: Specific human leucocyte antigen (HLA) alleles are not only associated with higher risk to develop multiple sclerosis (MS) and other autoimmune diseases, but also with the severity of various viral and bacterial infections. Here, we analyzed the most specific biomarker for MS, that is, the polyspecific intrathecal IgG antibody production against measles, rubella, and varicella zoster virus (MRZ reaction), for possible HLA associations in MS. METHODS: We assessed MRZ reaction from 184 Swiss patients with MS and clinically isolated syndrome (CIS) and 89 Swiss non-MS/non-CIS control patients, and performed HLA sequence-based typing, to check for associations of positive MRZ reaction with the most prevalent HLA alleles. We used a cohort of 176 Swedish MS/CIS patients to replicate significant findings. RESULTS: Whereas positive MRZ reaction showed a prevalence of 38.0% in MS/CIS patients, it was highly specific (97.7%) for MS/CIS. We identified HLA-DRB1*15:01 and other tightly linked alleles of the HLA-DR15 haplotype as the strongest HLA-encoded risk factors for a positive MRZ reaction in Swiss MS/CIS (odds ratio [OR], 3.90, 95% confidence interval [CI] 2.05-7.46, padjusted = 0.0004) and replicated these findings in Swedish MS/CIS patients (OR 2.18, 95%-CI 1.16-4.02, padjusted = 0.028). In addition, female MS/CIS patients had a significantly higher probability for a positive MRZ reaction than male patients in both cohorts combined (padjusted <0.005). INTERPRETATION: HLA-DRB1*15:01, the strongest genetic risk factor for MS, and female sex, 1 of the most prominent demographic risk factors for developing MS, predispose in MS/CIS patients for a positive MRZ reaction, the most specific CSF biomarker for MS. ANN NEUROL 2024;95:1112-1126.
Asunto(s)
Inmunoglobulina G , Esclerosis Múltiple , Humanos , Femenino , Masculino , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Adulto , Persona de Mediana Edad , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/genética , Cadenas HLA-DRB1/genética , Suecia/epidemiología , Estudios de Cohortes , Adulto Joven , Virus de la Rubéola/genética , Virus de la Rubéola/inmunología , Antígenos HLA/genética , Anticuerpos Antivirales/líquido cefalorraquídeo , Anticuerpos Antivirales/sangre , Alelos , Suiza/epidemiologíaRESUMEN
OBJECTIVES: During the COVID-19 pandemic, the risk of childhood infectious diseases was increased. Post-COVID-19 escalation of chickenpox cases, becoming an emerging public health concern. Thus, the study was designed to compare chickenpox prevalence and Varicella zoster virus (VZV) genotypes circulating before, during, and post-COVID-19 in Pakistan. METHODS: A total of 267 lesion specimens collected from tertiary care hospitals, and chickenpox outbreaks from Pakistan were analysed by a two-amplicon approach with phylogenetic analysis. RESULTS: Among suspected cases, overall 178/267 were VZV positive. Majority (84.2 %; 150/178) cases were of post-COVID-19 pandemic time. Small outbreaks occurred soon after COVID-19 in Rawalpindi and Islamabad (Pakistan), 40 positive cases out of 178 cases were outbreak cases. There was first time detection of the M4 genotype, which was significantly associated with disease severity (p = 0.0006) and post-COVID-19 chickenpox outbreaks in 2021 (77.9 %; 46/59; p < 0.00001). However, in pre-COVID-19 only M2 genotype was detected. The M2 prevalence varied from 2019 (100 %; 19/19) to 2022 (3.2 %; 3/91). However, the most prevalent strain of 2022 belonged to the M1 genotype (64.8 %; 59/91). CONCLUSION: A significant rise in chickenpox cases detected soon after COVID-19 in Pakistan, and oscillation of different VZV genotypes with first time detection of M4 genotype is an alarming situation. This demands further detailed genotypic studies on transmission dynamics of a rare M4 with other genotypes to protect the local population and restrict spread in other regions.
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COVID-19 , Varicela , Herpes Zóster , Humanos , Varicela/epidemiología , Varicela/diagnóstico , Pakistán/epidemiología , Filogenia , Pandemias , COVID-19/diagnóstico , COVID-19/epidemiología , Herpesvirus Humano 3/genética , Genotipo , Herpes Zóster/diagnóstico , Herpes Zóster/epidemiologíaRESUMEN
BACKGROUND: The varicella-zoster virus (VZV), belonging to the group of human α-herpesviruses, has yet to be developed as a platform for oncolytic virotherapy, despite indications from clinical case reports suggesting a potential association between VZV infection and cancer remission. METHODS: Here, we constructed oncolytic VZV candidates based on the vaccine strain vOka and the laboratory strain Ellen. These newly engineered viruses were subsequently assessed for their oncolytic properties in the human MeWo melanoma xenograft model and the mouse B16-F10-nectin1 melanoma syngeneic model. RESULTS: In the MeWo xenograft model, both vOka and Ellen exhibited potent antitumor efficacy. However, it was observed that introducing a hyperfusogenic mutation into glycoprotein B led to a reduction in VZV's effectiveness. Notably, the deletion of ORF8 (encodes viral deoxyuridine triphosphatase) attenuated the replication of VZV both in vitro and in vivo, but it did not compromise VZV's oncolytic potency. We further armed the VZV Ellen-ΔORF8 vector with a tet-off controlled mouse single-chain IL12 (scIL12) gene cassette. This augmented virus was validated for its oncolytic activity and triggered systemic antitumor immune responses in the immunocompetent B16-F10-nectin1 model. CONCLUSIONS: These findings highlight the potential of using Ellen-ΔORF8-tet-off-scIL12 as a novel VZV-based oncolytic virotherapy.
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Herpesvirus Humano 3 , Melanoma Experimental , Humanos , Animales , Ratones , Herpesvirus Humano 3/genética , Interleucina-12RESUMEN
BACKGROUND: The introduction of varicella vaccines into routine pediatric immunization programs has led to a considerable reduction in varicella incidence. However, there have been reports of varicella, herpes zoster, and meningitis caused by the vaccine strain of varicella-zoster virus (VZV), raising concerns. Establishing the relationship between the wild-type and vaccine strains in VZV infections among previously vaccinated individuals is crucial. Differences in the single nucleotide polymorphisms (SNPs) among vaccine strains can be utilized to identify the strain. In this study, we employed nanopore sequencing to identify VZV strains and analyzed clinical samples. METHODS: We retrospectively examined vesicle and cerebrospinal fluid samples from patients with VZV infections. One sample each of the wild-type and vaccine strains, previously identified using allelic discrimination real-time PCR and direct sequencing, served as controls. Ten samples with undetermined VZV strains were included. After DNA extraction, a long PCR targeting the VZV ORF62 region was executed. Nanopore sequencing identified SNPs, allowing discrimination between the vaccine and wild-type strains. RESULTS: Nanopore sequencing confirmed SNPs at previously reported sites (105,705, 106,262, 107,136, and 107,252), aiding in distinguishing between wild-type and vaccine strains. Among the ten unknown samples, nine were characterized as wild strains and one as a vaccine strain. Even in samples with low VZV DNA levels, nanopore sequencing was effective in strain identification. CONCLUSION: This study validates that nanopore sequencing is a reliable method for differentiating between the wild-type and vaccine strains of VZV. Its ability to produce long-read sequences is remarkable, allowing simultaneous confirmation of known SNPs and the detection of new mutations. Nanopore sequencing can serve as a valuable tool for the swift and precise identification of wild-type and vaccine strains and has potential applications in future VZV surveillance.
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Varicela , Herpes Zóster , Secuenciación de Nanoporos , Humanos , Niño , Herpesvirus Humano 3/genética , Estudios Retrospectivos , Polimorfismo de Longitud del Fragmento de Restricción , Reacción en Cadena de la Polimerasa/métodos , Vacuna contra la Varicela/genética , Herpes Zóster/prevención & control , ADN Viral/genéticaRESUMEN
To compare prevalence of positive PCR tests for herpesviruses between patients with and without a history of clinical corneal endothelial allograft rejection (AGR). Retrospective cross-sectional study with two-group comparison. A total of 307 aqueous humor (AH) samples from 235 Patients and 244 eyes who underwent penetrating keratoplasty or Descemet membrane endothelial keratoplasty or had a diagnostic AH aspiration due to clinical AGR between 2019 and 2023 were tested for DNA of herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). PCR test results were compared between the two groups (with/without AGR). Another sub-analysis examined the results of patients without a history of herpetic keratitis. A total of 8% of eyes with clinical AGR (9/108) had a positive PCR result for one of the herpesviruses (HSV:3, CMV:3, EBV:2, VZV:1). All patients in the group without AGR had negative PCR results for all previous viruses (0/136). The difference was statistically significant (p < 0.001). The sub-analysis of eyes without a history of herpetic keratitis also revealed significantly more positive herpes PCR results (7/87) in eyes with AGR than in eyes without AGR (0/42, p = 0.005). Clinical AGR after keratoplasty shows a significant correlation to viral replication. Herpetic infection and AGR could occur simultaneously and act synergistically. Timely differentiation between active herpetic infection and/or AGR is pivotal for proper treatment and graft preservation.