RESUMEN
Neurotropic viruses, characterized by their capacity to invade the central nervous system, present a considerable challenge to public health and are responsible for a diverse range of neurological disorders. This group includes a diverse array of viruses, such as herpes simplex virus, varicella zoster virus, poliovirus, enterovirus and Japanese encephalitis virus, among others. Some of these viruses exhibit high neuroinvasiveness and neurovirulence, while others demonstrate weaker neuroinvasive and neurovirulent properties. The clinical manifestations of infections caused by neurotropic viruses can vary significantly, ranging from mild symptoms to severe life-threatening conditions. Extracellular vesicles (EVs) have garnered considerable attention due to their pivotal role in intracellular communication, which modulates the biological activity of target cells via the transport of biomolecules in both health and disease. Investigating EVs in the context of virus infection is crucial for elucidating their potential role contribution to viral pathogenesis. This is because EVs derived from virus-infected cells frequently transfer viral components to uninfected cells. Importantly, EVs released by virus-infected cells have the capacity to traverse the blood-brain barrier (BBB), thereby impacting neuronal activity and inducing neuroinflammation. In this review, we explore the roles of EVs during neurotropic virus infections in either enhancing or inhibiting viral pathogenesis. We will delve into our current comprehension of the molecular mechanisms that underpin these roles, the potential implications for the infected host, and the prospective diagnostic applications that could arise from this understanding.
Asunto(s)
Barrera Hematoencefálica , Vesículas Extracelulares , Vesículas Extracelulares/virología , Vesículas Extracelulares/metabolismo , Humanos , Barrera Hematoencefálica/virología , Animales , Virus/patogenicidad , Virus/clasificación , Virosis/virología , Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Virus de la Encefalitis Japonesa (Especie)/fisiología , Herpesvirus Humano 3/patogenicidad , Herpesvirus Humano 3/fisiología , Enterovirus/patogenicidad , Enterovirus/fisiologíaRESUMEN
Herpes zoster (HZ), commonly known as shingles, is a painful blistering rash in dermatomal distribution, caused by the reactivation of varicella-zoster virus (VZV) that was acquired during a primary varicella infection. While commonly afflicting adults, cases of HZ in paediatric patients are infrequently reported. Such cases are predominantly reported in children who have had prior exposure to VZV, either during pregnancy, early childhood or have been vaccinated with live attenuated VZV. This report presents the first known case to our knowledge of HZ as the initial manifestation of a VZV infection in an immunocompetent toddler in the UK. The report details the chronology of the infection event and discusses the clinical context behind HZ presentations in paediatrics globally. It provides a compelling illustration of the uncommon presentation of VZV infection in an immunocompetent child devoid of antecedent virus exposure, thus meriting acknowledgement and potentially further investigation as to the cause.
Asunto(s)
Herpes Zóster , Herpesvirus Humano 3 , Humanos , Herpes Zóster/diagnóstico , Herpes Zóster/tratamiento farmacológico , Herpesvirus Humano 3/aislamiento & purificación , Antivirales/uso terapéutico , Aciclovir/uso terapéutico , Lactante , Masculino , Infección por el Virus de la Varicela-Zóster/diagnóstico , Infección por el Virus de la Varicela-Zóster/complicaciones , Infección por el Virus de la Varicela-Zóster/tratamiento farmacológico , Femenino , PreescolarRESUMEN
Background: Currently, evidence regarding the causal relationship between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome is limited and inconsistent. Therefore, this study employs Mendelian randomization (MR) methodology to investigate the causal relationship between the two. Methods: This study selected 110 single-nucleotide polymorphisms (SNPs) of primary immunodeficiency-related genes as instrumental variables (IVs). Genetic associations of primary immunodeficiency-related genes were derived from recent genome-wide association studies (GWAS) data on human plasma protein levels and circulating immune cells. Data on genes associated with varicella-zoster virus reactivation syndrome were obtained from the GWAS Catalog and FINNGEN database, primarily analyzed using inverse variance weighting (IVW) and sensitivity analysis. Results: Through MR analysis, we identified 9 primary immunodeficiency-related genes causally associated with herpes zoster and its subsequent neuralgia; determined causal associations of 20 primary immunodeficiency-related genes with three vascular lesions (stroke, cerebral aneurysm, giant cell arteritis); revealed causal associations of 10 primary immunodeficiency-related genes with two ocular diseases (retinopathy, keratitis); additionally, three primary immunodeficiency-related genes each were associated with encephalitis, cranial nerve palsy, and gastrointestinal infections. Conclusions: This study discovers a certain association between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome, yet further investigations are warranted to explore the specific mechanisms underlying these connections.
Asunto(s)
Estudio de Asociación del Genoma Completo , Herpesvirus Humano 3 , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Herpesvirus Humano 3/inmunología , Herpes Zóster/genética , Herpes Zóster/inmunología , Herpes Zóster/virología , Activación Viral , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Predisposición Genética a la Enfermedad , Infección por el Virus de la Varicela-Zóster/genética , Infección por el Virus de la Varicela-Zóster/inmunología , Síndromes de Inmunodeficiencia/genéticaRESUMEN
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
Mucosal-associated invariant T (MAIT) cells are unconventional T cells that respond to riboflavin biosynthesis and cytokines through TCR-dependent and -independent pathways, respectively. MAIT cell activation plays an immunoprotective role against several pathogens, however the functional capacity of MAIT cells following direct infection or exposure to infectious agents remains poorly defined. We investigated the impact of Varicella Zoster Virus (VZV) on blood-derived MAIT cells and report virus-mediated impairment of activation, cytokine production, and altered transcription factor expression by VZV infected (antigen+) and VZV exposed (antigen-) MAIT cells in response to TCR-dependent and -independent stimulation. Furthermore, we reveal that suppression of VZV exposed (antigen-) MAIT cells is not mediated by a soluble factor from neighbouring VZV infected (antigen+) MAIT cells. Finally, we demonstrate that VZV impairs the cytolytic potential of MAIT cells in response to riboflavin synthesising bacteria. In summary, we report a virus-mediated immune-evasion strategy that disarms MAIT cell responses.
Asunto(s)
Herpesvirus Humano 3 , Células T Invariantes Asociadas a Mucosa , Humanos , Células T Invariantes Asociadas a Mucosa/inmunología , Herpesvirus Humano 3/inmunología , Activación de Linfocitos/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Riboflavina/inmunología , Infección por el Virus de la Varicela-Zóster/inmunología , Infección por el Virus de la Varicela-Zóster/virología , Evasión Inmune/inmunología , Herpes Zóster/inmunología , Herpes Zóster/virologíaRESUMEN
Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.
Asunto(s)
Anticuerpos Antivirales , Encefalitis por Herpes Simple , Herpesvirus Humano 1 , Inmunoglobulina G , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Femenino , Masculino , Encefalitis por Herpes Simple/líquido cefalorraquídeo , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Anciano , Anticuerpos Antivirales/líquido cefalorraquídeo , Anticuerpos Antivirales/sangre , Adulto Joven , Adolescente , Herpesvirus Humano 3/inmunología , Reacción en Cadena de la Polimerasa , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Anciano de 80 o más Años , Niño , Líquido Cefalorraquídeo/virología , Líquido Cefalorraquídeo/inmunologíaAsunto(s)
Antivirales , Herpes Genital , Herpes Zóster , Herpesvirus Humano 3 , Humanos , Masculino , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Herpes Genital/diagnóstico , Herpes Genital/tratamiento farmacológico , Herpes Genital/patología , Herpes Genital/virología , Herpes Zóster/diagnóstico , Herpes Zóster/tratamiento farmacológico , Herpes Zóster/patología , Herpes Zóster/virología , Herpesvirus Humano 3/aislamiento & purificación , Anciano , Escroto/patología , Escroto/virología , Pene/patología , Pene/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/inmunologíaRESUMEN
The incidence of herpes zoster (HZ) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is significantly higher than that of the general public. Although routine antiviral prophylaxis is recommended, late-onset HZ has been highlighted, yet limited information is known about its clinical features and predictors. Here, we conducted a retrospective nested case-control study to identify patients with late-onset HZ, defined as a diagnosis of HZ after 1 year of transplantation, among allo-HSCT recipients between 2012 and 2017 at Peking University People's Hospital. Three controls were matched for each patient. A total of 201 patients developed late-onset HZ. Age over 20 years, absence of neutrophil engraftment by 14 days, mental disorders, immunosuppressant use at 1 year, and a peripheral CD4+/CD8+ ratio ≥0.5 at 1 year were independent risk factors, among which the CD4+/CD8+ ratio demonstrated good discriminative power for predicting late-onset HZ. For patients with a CD4+/CD8+ ratio <0.5, patient age, neutrophil engraftment time, mental disorders, and immunosuppressant use were potential risk factors. A stratification algorithm was accordingly established, classifying the transplant recipients into three risk groups. Whether the algorithm could facilitate the administration of posttransplant antiviral prophylaxis merits further validation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Herpes Zóster , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpes Zóster/virología , Herpes Zóster/epidemiología , Herpes Zóster/diagnóstico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Estudios de Casos y Controles , Trasplante Homólogo/efectos adversos , Adulto Joven , Medición de Riesgo , Antivirales/uso terapéutico , Incidencia , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Relación CD4-CD8 , Adolescente , Factores de Tiempo , Anciano , Herpesvirus Humano 3/inmunologíaRESUMEN
Purpose: Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response. Methods: VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared. Results: The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation. Conclusion: The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.
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Adyuvantes Inmunológicos , Inmunidad Celular , Ratones Endogámicos C57BL , Nanopartículas , Vacunas de Subunidad , Animales , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Nanopartículas/química , Adyuvantes Inmunológicos/administración & dosificación , Femenino , Vacunas de ARNm , Ratones , Herpesvirus Humano 3/inmunología , Anticuerpos Antivirales/sangre , Inmunización Secundaria/métodos , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/administración & dosificación , Vacuna contra el Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/administración & dosificación , LiposomasRESUMEN
INTRODUCTION: The incidence of varicella in Canada has decreased by almost 99% since vaccination was introduced. However, variation in the timing and eligibility of vaccination programs across the country has resulted in some cohorts being under-vaccinated and therefore potentially susceptible to infection. METHODS: We used nationally representative specimens from the Biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) as well as residual specimens from Ontario collected between 2009-2014 to estimate population immunity across age-groups and geography, and identify any groups at increased risk of varicella infection. RESULTS: The weighted proportion of specimens with antibody levels above the threshold of protection was 93.6% (95% CI: 92.4, 95.0). Protection was lowest among those aged 3-5 years (54.3%; 95% CI: 47.3, 61.4), but increased with age. Individuals born outside Canada had more than twice the odds of varicella susceptibility than those born in Canada (aOR: 2.7; 95% CI: 1.4, 5.0; p = 0.004). There were no differences by sex or geography within Canada, and there were no statistically significant differences when Ontario CHMS sera were compared to Ontario residual sera, apart from in participants aged 12-19 year age-group, for whom the CHMS estimate (91.2%; 95% CI: 86.7, 95.7) was significantly higher (p = 0.03) than that from residual specimens (85.9%, 95% CI: 81.1, 90.8). DISCUSSION: Varicella immunity in Canada is changing. Children appear to have low population immunity, placing them at greater risk of infection and at increased risk of severe disease as they age. Our results underscore the importance of performing periodic serosurveys to monitor further population immunity changes as the proportion of vaccine-eligible birth-cohorts increases, and to continually assess the risk of outbreaks.
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Varicela , Humanos , Varicela/epidemiología , Varicela/inmunología , Varicela/prevención & control , Adolescente , Niño , Preescolar , Femenino , Masculino , Canadá/epidemiología , Adulto , Adulto Joven , Persona de Mediana Edad , Lactante , Vacuna contra la Varicela/inmunología , Vacunación , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Herpesvirus Humano 3/inmunologíaRESUMEN
Herpes zoster (HZ), resulting from the reactivation of the varicella-zoster virus, is a significant disease. This study aimed to explore the factors influencing sensory neuron involvement in HZ at different locations and its association with postherpetic neuralgia (PHN). A total of 3143 cases were retrieved from an electronic medical record system, including 2676 cases of HZ and 467 cases of PHN. Gender, age, site of onset, past surgical history, and comorbidities were analyzed using a multifactorial logistic regression model. The results revealed correlations between age, gender, comorbidities (diabetes, coronary heart disease, percutaneous coronary intervention [PCI]), and sensory neuron involvement in HZ. Specifically, older age, female gender, and comorbid conditions such as diabetes/coronary heart disease were associated with sacral dorsal root ganglion (DRG) involvement, while PCI history was associated with lumbar DRG involvement. Additionally, sensory neuron involvement at different locations by HZ was linked to PHN. Furthermore, independent risk factors for PHN included thoracic DRG involvement, older age, and comorbidities (diabetes, surgical history, malignancy). It is crucial to prevent damage to the DRG, especially in individuals with comorbidities, through activities avoidance and active treatment, to minimize the occurrence of PHN.
Asunto(s)
Herpes Zóster , Neuralgia Posherpética , Humanos , Herpes Zóster/epidemiología , Herpes Zóster/complicaciones , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Neuralgia Posherpética/epidemiología , Factores de Riesgo , Anciano de 80 o más Años , Adulto , Comorbilidad , Ganglios Sensoriales/virología , Herpesvirus Humano 3 , Factores de Edad , Ganglios Espinales/virología , Adulto Joven , Factores SexualesRESUMEN
The patient, a 36-year-old female, had no previous history of shingles. She was admitted to the hospital due to nausea and lightheadedness. Upon admission, she was diagnosed with bilateral medial medullary infarcts. She received treatment with intravenous edaravone and argatroban, as well as antiplatelet therapy with aspirin and clopidogrel. However, her dysphagia, dysarthria, and paraplegia worsened. Due to changes in the lesion of the basilar artery on brain |MRA, we suspected the possibility of basilar artery dissection, and discontinued antiplatelet therapy. Subsequent imaging studies suggested vasculitis. After examining the cerebrospinal fluid, we diagnosed varicella-zoster virus (VZV) vasculopathy. Based on this diagnosis, we administered steroid pulse therapy for three days, started intravenous acyclovir, and resumed antithrombotic therapy with clopidogrel. Prednisone was administered for five days. Biochemical tests revealed an elevated D-dimer level. Due to the presence of lower extremity venous thrombus, clopidogrel was replaced with apixaban. The acyclovir infusion was discontinued due to observed acyclovir-induced neutropenia. These treatments improved neurological symptoms, circumflex thickening of the basilar artery, and contrast effects in the same area. On the 70th day, the patient was transferred to the hospital for rehabilitation. It is important to consider VZV angiopathy as a potential cause of juvenile cerebral infarction accompanying progressive basilar artery stenosis, regardless of the presence or absence of a skin rash.
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Herpesvirus Humano 3 , Humanos , Femenino , Adulto , Infección por el Virus de la Varicela-Zóster/complicaciones , Infección por el Virus de la Varicela-Zóster/tratamiento farmacológico , Infección por el Virus de la Varicela-Zóster/diagnóstico , Aciclovir/administración & dosificación , Quimioterapia por Pulso , Bulbo Raquídeo , Infartos del Tronco Encefálico/etiología , Infartos del Tronco Encefálico/tratamiento farmacológico , Antivirales/administración & dosificación , Resultado del Tratamiento , Clopidogrel/administración & dosificación , Piridonas/administración & dosificación , PirazolesRESUMEN
Severe haematological diseases and lymphoid malignancies require bone marrow (BM)-suppressive treatments. Knowledge regarding the impact of BM-suppressive treatments on children's memory T cells is very limited. Memory T cells play a crucial role in defending against herpesviruses, which is particularly relevant in paediatric cancer care. We studied 53 children in total; 34 with cancer and 2 with severe haematological disorders, with some receiving BM-suppressive treatment with or without allogeneic-haematopoietic stem cell transplantation (allo-HSCT), alongside 17 healthy controls. We focused on peripheral blood proportions of memory T-cell subsets using flow cytometry and analysed cytokine-secreting T cells with a four-parameter FluoroSpot assay in response to T-cell mitogen and varicella zoster virus (VZV) peptides. Patients on BM-suppressive treatment showed increased clusters of differentiation (CD)4+ and CD8+ effector memory (TEM)/terminally differentiated effector (TEFF) T cells compared to the healthy controls. They also exhibited, amongst other things, when compared to the healthy controls, a reduced total number of cytokine-secreting cells, by means of interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-22, following mitogen activation. A diminished IFN-γ response among the children with BM-suppressive treatment was observed upon VZV-peptide stimulation, compared to the healthy children. Collectively, the findings herein indicate that the children who are undergoing or have finished BM-suppressive treatment display qualitative differences in their T-cell memory compartment, potentially increasing their susceptibility to severe viral infections and impacting their immunotherapy, which relies on the functional ability of autologous T cells.
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Herpesvirus Humano 3 , Interferón gamma , Humanos , Niño , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Masculino , Femenino , Interferón gamma/metabolismo , Preescolar , Adolescente , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/inmunología , Linfocitos T/metabolismo , Médula Ósea , Células T de Memoria/inmunologíaRESUMEN
Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that causes neurological manifestations either as a complication of primary infection or reactivation. VZV induced neurological diseases have a good prognosis when confirmed early and treated with anti-viral therapy. Myelitis, encephalitis, ventriculitis or meningitis can occur without a telltale rash in immunocompetent and immunocompromised individuals making the diagnosis difficult. We analyzed CSF and serum samples from 30 unvaccinated study participants (17 male and 13 female) to determine the presence of VZV DNA by PCR in CSF and to estimate serum and CSF anti-VZV IgG and albumin levels in participants with neurological manifestations with/without rash. Anti-VZV IgG was detected in CSF (n = 22, [73%]) and serum (n = 29, [97%]) of pediatric and adult participants. Anti-VZV IgG were detected in CSF of participants with varied clinical presentation altered sensorium (n = 8, [36%]), meningitis (n = 4, [18%]), acute febrile illness (n = 3, [14%], encephalopathy/meningoencephalitis (n = 2, [9%]), irritability (n = 2, [9%]) and each patient from cerebrovascular stroke, demyelinating disorder and febrile seizure (n = 1, [4.5%]). VZV DNA was detected from one participant and CSF serum albumin levels were elevated in 53% of study participants. VZV DNA is present up to 1-2 weeks post onset of disease, after which anti-VZV antibody may be the only indicator of disease and therefore both VZV DNA and anti-VZV IgG need to be tested for in CSF. As VZV DNA and VZV IgG antibody are both good indicators of VZV reactivation, routine testing would result in reduced morbidity and mortality by early detection of disease and antiviral treatment.
Asunto(s)
Anticuerpos Antivirales , Herpesvirus Humano 3 , Inmunoglobulina G , Humanos , Masculino , Femenino , Herpesvirus Humano 3/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Adolescente , Persona de Mediana Edad , Niño , Preescolar , ADN Viral/sangre , ADN Viral/líquido cefalorraquídeo , Adulto Joven , Anciano , Varicela/virología , Varicela/inmunología , Varicela/diagnóstico , Varicela/sangre , LactanteRESUMEN
Varicella zoster virus (VZV) reactivates from ganglionic sensory neurons to produce herpes zoster (shingles) in a unilateral dermatomal distribution, typically in the thoracic region. Reactivation not only heightens the risk of stroke and other neurological complications but also increases susceptibility to co-infections with various viral and bacterial pathogens at sites distant from the original infection. The mechanism by which VZV results in complications remote from the initial foci remains unclear. Small extracellular vesicles (sEVs) are membranous signaling structures that can deliver proteins and nucleic acids to modify the function of distal cells and tissues during normal physiological conditions. Although viruses have been documented to exploit the sEV machinery to propagate infection, the role of non-infectious sEVs released from VZV-infected neurons in viral spread and disease has not been studied. Using multi-omic approaches, we characterized the content of sEVs released from VZV-infected human sensory neurons (VZV sEVs). One viral protein was detected (immediate-early 62), as well as numerous immunosuppressive and vascular disease-associated host proteins and miRNAs that were absent in sEVs from uninfected neurons. Notably, VZV sEVs are non-infectious yet transcriptionally altered primary human cells, suppressing the antiviral type 1 interferon response and promoting neuroinvasion of a secondary pathogen in vivo. These results challenge our understanding of VZV infection, proposing that the virus may contribute to distant pathologies through non-infectious sEVs beyond the primary infection site. Furthermore, this study provides a previously undescribed immune-evasion mechanism induced by VZV that highlights the significance of non-infectious sEVs in early VZV pathogenesis. IMPORTANCE: Varicella zoster virus (VZV) is a ubiquitous human virus that predominantly spreads by direct cell-cell contact and requires efficient and immediate host immune evasion strategies to spread. The mechanisms of immune evasion prior to virion entry have not been fully elucidated and represent a critical gap in our complete understanding of VZV pathogenesis. This study describes a previously unreported antiviral evasion strategy employed by VZV through the exploitation of the infected host cell's small extracellular vesicle (sEV) machinery. These findings suggest that non-infectious VZV sEVs could travel throughout the body, affecting cells remote from the site of infection and challenging the current understanding of VZV clinical disease, which has focused on local effects and direct infection. The significance of these sEVs in early VZV pathogenesis highlights the importance of further investigating their role in viral spread and secondary disease development to reduce systemic complications following VZV infections.