Varicella-zoster virus-related neurological complications: From infection to immunomodulatory therapies.

The Varicella-zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV-associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune-mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune-mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV-induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV-related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV-induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections.

Identification and characterization of Varicella Zoster Virus circular RNA in lytic infection.

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.

Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity.

Autophagy is a degradational pathway with pivotal roles in cellular homeostasis and survival, including protection of neurons in the central nervous system (CNS). The significance of autophagy as antiviral defense mechanism is recognized and some viruses hijack and modulate this process to their advantage in certain cell types. Here, we present data demonstrating that the human neurotropic herpesvirus varicella zoster virus (VZV) induces autophagy in human SH-SY5Y neuronal cells, in which the pathway exerts antiviral activity. Productively VZV-infected SH-SY5Y cells showed increased LC3-I-LC3-II conversion as well as co-localization of the viral glycoprotein E and the autophagy receptor p62. The activation of autophagy was dependent on a functional viral genome. Interestingly, inducers of autophagy reduced viral transcription, whereas inhibition of autophagy increased viral transcript expression. Finally, the genotype of patients with severe ocular and brain VZV infection were analyzed to identify potential autophagy-associated inborn errors of immunity. Two patients expressing genetic variants in the autophagy genes ULK1 and MAP1LC3B2, respectively, were identified. Notably, cells of both patients showed reduced autophagy, alongside enhanced viral replication and death of VZV-infected cells. In conclusion, these results demonstrate a neuro-protective role for autophagy in the context of VZV infection and suggest that failure to mount an autophagy response is a potential predisposing factor for development of severe VZV disease.

Varicella zoster virus outbreak in a long-term care unit of a tertiary care hospital in northern India.

Nosocomial outbreak of varicella zoster virus (VZV) has been reported when susceptible individuals encounter a case of chicken pox or shingles. A suspected VZV outbreak was investigated in a 50-bedded in-patient facility of Physical Medicine and Rehabilitation in a tertiary care multispecialty hospital. A 30-year-old female patient admitted with Pott's spine was clinically diagnosed with chicken pox on 31 December 2022. The following week, four more cases were identified in the same ward. All cases were diagnosed as laboratory-confirmed varicella zoster infection by PCR. Primary case was a housekeeping staff who was clinically diagnosed with chicken pox 3 weeks prior (9 December 2022). He returned to work on eighth day of infection (17 December 2022) after apparent clinical recovery but before the lesions had crusted over. Thirty-one HCWs were identified as contacts a and three had no evidence of immunity. Two of these susceptible HCWs had onset of chickenpox shortly after first dose of VZV vaccination was inoculated. All cases recovered after treatment with no reported complications. VZV infection is highly contagious in healthcare settings with susceptible populations. Prompt identification of cases and implementation of infection prevention and control measures like patient isolation and vaccination are essential for the containment of outbreaks.

Guillain-Barre syndrome of acute motor axonal neuropathy (AMAN) type associated with herpes zoster: a case report.

Guillain Barre syndrome (GBS) following Varicella zoster is a rare presentation and has only been reported in a few cases around the world. Of the reported cases, the type of GBS is not specified in the majority, and where specified is of the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) type. We report a case of acute motor axonal neuropathy (AMAN) type GBS following herpes zoster in a 27-year-old male who presented with bilateral lower limb weakness and left sided lower motor neuron type facial nerve palsy a week after herpes zoster infection.

Construction of a pathological model of skin lesions in acute herpes zoster virus infection and its molecular mechanism.

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.

A mathematical model for varicella-zoster and HIV co-dynamic supported by numerical simulations.

The prevalence of the varicella-zoster virus (VZV) and its correlation underscore its impact on a significant segment of the population. Notably contagious, VZV serves as a risk factor for the manifestation of HIV/AIDS, with its reactivation often signaling the onset of immunodeficiency. Recognizing the concurrent existence of these two diseases, this study focuses on the co-infection dynamics through a deterministic mathematical model. The population is categorized into seven exclusive groups, considering the complexities arising from the interplay of HIV and Zoster. We establish the non-negativity and boundedness of solutions, examine equilibrium points, calculate basic reproduction numbers via the next-generation matrix approach, and analyze the existence and local stabilities of equilibriums using the Routh-Hurwitz stability criteria. The numerical simulations reveal that the model converges to an endemic equilibrium point when the reproduction number exceeds unity. The primary objectives of this study are to comprehensively understand the transmission dynamics of HIV and Zoster in a co-infected population and to provide valuable insights for developing effective intervention strategies. The findings emphasize the importance of addressing these co-infections to mitigate their impact on public health.

A Case of Varicella Zoster and Mpox Coinfection in a Patient Living With HIV.

ABSTRACT: We present a case of recurrent, cutaneous mpox with coinfection of disseminated varicella zoster in an immunocompromised patient with poorly controlled HIV. This case demonstrates the importance of maintaining a high index of suspicion for mpox despite prior infection and vaccination, as suboptimal immune response is possible in immunocompromised patients, and also noting the potential for coinfection necessitating timely diagnosis and appropriate testing.

Metabolomics profiling in predicting of post-herpetic neuralgia induced by varicella zoster.

To explore potential metabolomics biomarkers in predicting post-herpetic neuralgia (PHN) induced by herpes zoster (HZ). A total of 90 eligible patients were prospectively enrolled and assigned into an acute pain (ACP) group and a PHN group. Serum samples were collected before clinical intervention to perform metabolomics profiling analyses using gas chromatography mass spectrometry (GC-MS). Key metabolites were identified using partial least squares discriminant analysis (PLS-DA). A binary logistic regression was used to build a combined biomarker model to predict PHN from ACP. The discriminating efficiency of the combined biomarker model was investigated and validated by internal validation. Six metabolites were identified as the key metabolites related to PHN. All these metabolites (N-Acetyl-5-hydroxytryptaMine, glucose, dehydroascorbic acid, isopropyl-beta-D-thiogalactopyranoside, 1,5-anhydro-D-sorbitol, and glutamic acid) were found elevated in the PHN group. Pathway analyses showed that glucose-alanine cycle, tryptophan metabolism, tyrosine metabolism, lactose degradation, malate-aspartate shuttle were top five metabolic pathways evolved in PHN. The AUC was 0.85 (95% CI 0.76-0.93) for the combined biomarker model, and was 0.91 (95% CI 0.84-1.00) for the internal validation data set to predict PHN. Metabolomics analyses of key metabolites could be used to predict PHN induced by HZ.

Clinical characteristics and predictors of human mpox outcome during the 2022 outbreak in Nigeria: a cohort study.

BACKGROUND: Research from sub-Saharan Africa that contributes to our understanding of the 2022 mpox (formerly known as monkeypox) global outbreak is insufficient. Here, we describe the clinical presentation and predictors of severe disease among patients with mpox diagnosed between Feb 1, 2022, and Jan 30, 2023 in Nigeria. METHODS: We did a cohort study among laboratory-confirmed and probable mpox cases seen in 22 mpox-treatment centres and outpatient clinics across Nigeria. All individuals with confirmed and probable mpox were eligible for inclusion. Exclusion criteria were individuals who could not be examined for clinical characterisation and those who had unknown mortality outcomes. Skin lesion swabs or crust samples were collected from each patient for mpox diagnosis by PCR. A structured questionnaire was used to document sociodemographic and clinical data, including HIV status, complications, and treatment outcomes from the time of diagnosis to discharge or death. Severe disease was defined as mpox associated with death or with a life-threatening complication. Two logistic regression models were used to identify clinical characteristics associated with severe disease and potential risk factors for severe disease. The primary outcome was the clinical characteristics of mpox and disease severity. FINDINGS: We enrolled 160 people with mpox from 22 states in Nigeria, including 134 (84%) adults, 114 (71%) males, 46 (29%) females, and 25 (16%) people with HIV. Of the 160 patients, distinct febrile prodrome (n=94, 59%), rash count greater than 250 (90, 56%), concomitant varicella zoster virus infection (n=48, 30%), and hospital admission (n=70, 48%) were observed. Nine (6%) of the 160 patients died, including seven (78%) deaths attributable to sepsis. The clinical features independently associated with severe disease were a rash count greater than 10 000 (adjusted odds ratio 26·1, 95% CI 5·2-135·0, p<0·0001) and confluent or semi-confluent rash (6·7, 95% CI 1·9-23·9). Independent risk factors for severe disease were concomitant varicella zoster virus infection (3·6, 95% CI 1·1-11·5) and advanced HIV disease (35·9, 95% CI 4·1-252·9). INTERPRETATION: During the 2022 global outbreak, mpox in Nigeria was more severe among those with advanced HIV disease and concomitant varicella zoster virus infection. Proactive screening, management of co-infections, the integration and strengthening of mpox and HIV surveillance, and preventive and treatment services should be prioritised in Nigeria and across Africa. FUNDING: None.

Genomic characterization of the first mpox and varicella-zoster co-infection in Pakistan (2023) through next-generation sequencing.

The global mpox outbreak spanning 2022-2023 has affected numerous countries worldwide. In this study, we present the first report on the detection, whole-genome sequence, and coinfection of the mpox virus and varicella zoster virus (VZV) from Pakistan. During April-May 2023, samples from 20 suspected cases of mpox were tested at the National Institutes of Health, Islamabad among which 4 tested positive. All four cases had a travel history of Saudi Arabia. All the suspected samples were processed by using a Zymo research kit for DNA extraction, followed by qRT-PCR amplification by using a DaAn Gene detection kit for the mpox virus. Further, two of the positive samples with a low Ct value (<20) were subjected to whole-genome sequencing using a metagenomic approach on the iSeq (Illumina) platform. The sequencing results revealed Clade IIb and genotype A.2.1 of MPXV, which clustered with viruses from Slovenia and the UK in July and June 2022, respectively. Our analysis identified two novel nonsynonymous substitutions in mpox virus, namely V98I in OPG046 and P600S in OPG109. Furthermore, we successfully retrieved the complete genome of VZV from the same sample, belonging to Clade 5. This study represents the first positive case of MPXV in Pakistan and the coinfection of mpox and VZV by using a metagenome approach providing insights into their complete genomes. Our results highlight the importance of surveillance at the point of entries, strengthening lab capacities including next-generation sequencing, and using differential diagnosis for timely and accurate detection of mpox cases.

Síndrome de Ramsay Hunt en paciente epiléptico en Santander, Colombia: Reporte de caso / Ramsay Hunt Syndrome in an epileptic patient in Santander, Colombia: Case report

El Síndrome de Ramsay Hunt es una entidad infrecuente, con una incidencia de 5 por cada 100.000 personas por año. Esta condición se caracteriza por una reactivación del virus de la varicela-zoster en el nervio facial. Su diagnóstico implica un reto para el médico puesto que suele ser netamente clínico, con la aparición de una triada consistente en: otalgia, parálisis facial ipsilateral y vesículas en el canal auditivo. El objetivo del artículo es presentar el caso de una mujer de 49 años de edad, con antecedente de epilepsia en tratamiento anticonvulsivante, quien ingresa con la triada clínica antes descrita, asociada a visión borrosa derecha y vértigo. La paciente fue tratada con antivirales y corticoides orales, presentando una resolución clínica favorable dado una reducción de más del 50% de las lesiones cutáneas. No se identificaron diferencias respecto a la presentación clínica de este síndrome al compararse con pacientes no epilépticos.

Ramsay Hunt Syndrome is a rare entity, with an incidence of 5 per 100,000 people per year. This condition is characterized by a reactivation of the varicella-zoster virus in the facial nerve. Its diagnosis implies a challenge for the physician since it is usually a clinical diagnosis, with the appearance of a clinical triad consisting of: otalgia, ipsilateral facial paralysis and vesicles in the ear canal. The objective of the article is to present the case of a 49-year-old woman, with a history of epilepsy receiving anticonvulsant treatment, who was admitted with the aforementioned clinical triad, associated with blurred right vision and vertigo. The patient was treated with oral antiviral management and oral corticosteroids, presenting a favorable clinical resolution given a reduction of more than 50% of the skin lesions. No differences were identified regarding the clinical presentation of this syndrome when compared with non-epileptic patients.

Lack of strong innate immune reactivity renders macrophages alone unable to control productive Varicella-Zoster Virus infection in an isogenic human iPSC-derived neuronal co-culture model.

With Varicella-Zoster Virus (VZV) being an exclusive human pathogen, human induced pluripotent stem cell (hiPSC)-derived neural cell culture models are an emerging tool to investigate VZV neuro-immune interactions. Using a compartmentalized hiPSC-derived neuronal model allowing axonal VZV infection, we previously demonstrated that paracrine interferon (IFN)-α2 signalling is required to activate a broad spectrum of interferon-stimulated genes able to counteract a productive VZV infection in hiPSC-neurons. In this new study, we now investigated whether innate immune signalling by VZV-challenged macrophages was able to orchestrate an antiviral immune response in VZV-infected hiPSC-neurons. In order to establish an isogenic hiPSC-neuron/hiPSC-macrophage co-culture model, hiPSC-macrophages were generated and characterised for phenotype, gene expression, cytokine production and phagocytic capacity. Even though immunological competence of hiPSC-macrophages was shown following stimulation with the poly(dA:dT) or treatment with IFN-α2, hiPSC-macrophages in co-culture with VZV-infected hiPSC-neurons were unable to mount an antiviral immune response capable of suppressing a productive neuronal VZV infection. Subsequently, a comprehensive RNA-Seq analysis confirmed the lack of strong immune responsiveness by hiPSC-neurons and hiPSC-macrophages upon, respectively, VZV infection or challenge. This may suggest the need of other cell types, like T-cells or other innate immune cells, to (co-)orchestrate an efficient antiviral immune response against VZV-infected neurons.

A survival case of visceral disseminated varicella zoster virus infection in a patient with systemic lupus erythematosus.

BACKGROUND: Visceral disseminated varicella zoster virus (VZV) infection is a rare but life-threatening complication in immunosuppressed patients. Herein, we report a survival case of visceral disseminated VZV infection in a patient with systemic lupus erythematosus (SLE). CASE PRESENTATION: A 37-year-old woman was diagnosed as SLE and initial induction therapy was started. Two months after starting the immunosuppressive therapy consisting of 40 mg of prednisolone (PSL) and 1500 mg of mycophenolate mofetil (MMF) daily, she suddenly developed strong abdominal pain, which was required opioid analgesics, followed by systemic skin blisters, which were diagnosed as varicella. Laboratory findings showed rapid exacerbation of severe liver failure, coagulation abnormalities and increased numbers of blood VZV deoxyribonucleic acid (DNA). Therefore, she was diagnosed as visceral disseminated VZV infection. Multidisciplinary treatment with acyclovir, immunoglobulin and antibiotics was started, the dose of PSL was reduced, and MMF was withdrawn. By their treatment, her symptoms were resolved and she finally discharged. CONCLUSIONS: Our case highlights the importance of a clinical suspicion of visceral disseminated VZV infections, and the necessity of immediate administration of acyclovir and reduced doses of immunosuppressant to save patients with SLE.

Disseminated varicella-zoster virus infection in an aplastic anemia- paroxysmal nocturnal hemoglobinuria syndrome patient: A case report.

Background: Varicella-zoster virus (VZV) is a common and widespread human-restricted pathogen. It is famous for its dermatological manifestations, such as varicella and herpes zoster. Patients with aplastic anemia-paroxysmal nocturnal hemoglobinuria (AA-PNH) syndrome complicated with fatal disseminated varicella zoster virus infection are very rare and in danger. Patient concerns: A 26-year-old man with a history of AA-PNH syndrome was receiving cyclosporine and corticosteroid treatment in the hematology department. During his hospitalization in our hospital, he developed fever, abdominal pain, and lower back pain, and his face, penis, trunk, and limbs developed itchy rash. Subsequently, the patient had to undergo cardiopulmonary resuscitation because of sudden cardiac arrest, and be transferred to ICU for treatment. It was presumed that the cause is unknown severe sepsis. The patient's condition quickly progressed to multiple organ failure, accompanied by liver, respiratory, and circulatory failure, and signs of disseminated intravascular coagulation. Unfortunately, the patient died after 8 h of active treatment. Finally, we collected all the evidence and concluded that the patient died of AA-PNH syndrome combined with poxzoster virus. Conclusion: AA-PNH syndrome patients treated with steroids and immunosuppressants are prone to various infections, considering that herpes virus infection with chickenpox and rash as the initial manifestations is characterized by rapid progress and often accompanied by serious complications. It is more difficult to distinguish it from AA-PNH syndrome with skin bleeding points. If it is not identified in time, it may delay the treatment opportunity, make the condition worse, and cause serious adverse prognosis. Therefore, clinicians need to pay attention to it.