SIV-specific antibodies protect against inflammasome-driven encephalitis in untreated macaques.

Viral encephalitis is a growing public health threat with limited diagnostic and treatment options. Simian immunodeficiency virus (SIV)-infected macaques are an established model for human immunodeficiency virus (HIV), and approximately 60% of untreated pigtail macaques rapidly progress to characteristic SIV encephalitis (SIVE). The immune responses of SIV-infected macaques are investigated in plasma, cerebrospinal fluid (CSF), and brain tissue to determine correlates with SIVE pathology. Macaques with SIVE show myeloid-dominant brain lesions with inflammasome activation in infected and bystander cells, as assessed by interleukin (IL)-1ß, IL-18, and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and elevations in monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and tumor necrosis factor alpha (TNF-α). SIV-specific immunoglobulin (Ig)G in plasma and CSF is predictive of SIVE as early as 21 days post-inoculation; animals with SIVE continue to show negligible seroconversion 3 months after infection. This dichotomy in immune responses, wherein some macaques fail to initiate robust IgG responses and subsequently develop SIVE, provides insight into the pathogenesis and heterogeneous outcomes in viral encephalitis.

A Dual Diagnostic Dilemma: Viral Encephalitis and Cerebral Venous Thrombosis.

Herpes encephalitis is caused by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). One of the infrequent complications of herpes encephalitis is cerebral venous thrombosis (CVT) because of the inflammation in the brain parenchyma. We report a unique and challenging case of a 14-year-old female patient presenting with confusion, headache, and fever. On examination, there was no neck rigidity and a negative Kernig's sign with no focal neurological deficits. Systemic examination was done to rule out other systems as a cause for her symptoms, and she was empirically treated as a case of encephalitis. An initial computed tomography (CT) scan of the brain without contrast was normal except for a subtle hypoattenuating area involving the right thalamus. Cerebrospinal fluid (CSF) analysis revealed viral infection while we awaited the results of CSF polymerase chain reaction (PCR) and culture analysis for specific microorganisms. Her Glasgow Coma Scale (GCS) deteriorated following an episode of generalized tonic-clonic seizure, and she was subsequently catheterized and an enteral feeding tube (nasogastric tube) was passed. CSF PCR detected HSV-1. Magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) of the brain with contrast revealed encephalitis with superior sagittal sinus, transverse sinus, straight sinus, and vein of Galen thrombosis yielding a diagnosis of HSV encephalitis with concurrent cerebral venous thrombosis. Hence, this required a very specialized and cautious approach to her treatment. She was started on intravenous acyclovir and subcutaneous enoxaparin, and she recovered over the next few days. She did, however, develop acyclovir-induced renal toxicity in the absence of another offending agent, and the dose of the acyclovir was adjusted accordingly. A diagnosis of CVT, although rarely described, should be systematically suspected in patients with HSV encephalitis presenting with sudden deterioration or unexpected neurological findings in the early phase of treatment or inadequate response to treatment for better management and outcomes.

Speech-language performance and comorbid disorders in children with perisylvian syndrome induced by viral encephalitis.

Importance: Viral encephalitis is one of the main causes of the perisylvian syndrome, which can cause damage to children's language-speech, feeding, and swallowing functions. Comprehensive assessment of language-speech and swallowing function and comorbidity research on these children will help children's rehabilitation workers to better understand the disease and strengthen the systematic management of comorbid disorders. Objective: To describe speech and language pathology and the occurrence of comorbid disorders in children with perisylvian syndrome induced by viral encephalitis. Methods: Twenty-two children with acquired perisylvian syndrome were recruited in this study. Language and speech functions, including oral motor function, swallowing function, language ability, and dysarthria were assessed in these patients. Craniocerebral magnetic resonance imaging (MRI), electroencephalogram examination, and intelligence evaluation were performed to determine brain lesions and comorbid disorders. Results: All children exhibited different degrees of oral movement, dysphagia, and speech and language disorders. There was a significant difference between expressive and receptive language ability (P < 0.05). There were 10, 8, and 12 children who had an intellectual disability, limb disability, and epilepsy, respectively. In addition to the damage of the peri-tegmental cortex found in MRI, thalamus lesions occurred in 19 cases and white matter involvement in six cases. Interpretation: Children with acquired perisylvian syndrome caused by viral encephalitis are characterized by persistent pseudobulbar dysfunction, speech and language impairment, and orofacial diplegia. They have a high probability of secondary epilepsy and are prone to motor and cognitive impairment, which need systematic management.

Post-Herpetic Anti-NMDAR Encephalitis in Denmark: Current Status and Future Challenges.

It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning.

The Clinical Manifestations, Risk Factors, Etiologies, and Outcomes of Adult Patients with Infectious Meningitis and Encephalitis: Single Center Experience.

(1) Background: Central nervous system (CNS) infections, including meningitis and encephalitis, are serious conditions which are associated with high morbidity and mortality. This study aims to identify the clinical manifestations, etiologies, and outcomes of meningitis and encephalitis in adult patients in Saudi Arabia, addressing the current gap in understanding these conditions within this population. (2) Methods: This is a single-center retrospective study which included all adult patients diagnosed with meningitis and encephalitis from March 2016 to May 2022. (3) Results: This study found that most cases of meningitis and encephalitis occurred due to unknown pathogens. Pretreatment with antibiotics prior to lumbar puncture (LP) was found in 71.2% of patients with meningitis. Altered mental status and seizures were common presenting symptoms among patients with encephalitis while altered mental status and fever were common among patients with meningitis. (4) Conclusions: Adherence to guidelines in treating meningitis and encephalitis and performing LPs in a timely manner are important. Establishing national biobanks with biological samples from patients suspected of having meningitis or encephalitis will significantly enhance our understanding of these conditions in Saudi Arabia.

Acute Hemorrhagic Leukoencephalitis in a Patient With Hepatitis B.

Acute hemorrhagic leukoencephalitis (AHLE), also known as Weston-Hurst syndrome or Hurst disease, is a rare and rapidly progressive form of acute disseminated encephalomyelitis. It is characterized by severe inflammation, hemorrhage, and necrosis within the white matter of the brain. AHLE often follows an upper respiratory infection or other systemic illnesses, suggesting a potential post-infectious autoimmune mechanism. The disease is associated with a high mortality rate and significant disability among survivors. We present the case of a 46-year-old Indian woman with a history of chronic hepatitis B (HBV) who presented with an insidious onset of right-sided limb weakness and bi-frontal headaches. Initial brain MRIs showed features of tumefactive demyelination. Despite aggressive treatment with intravenous (IV) methylprednisolone, IV immunoglobulin, and anti-edema measures, the patient's condition rapidly deteriorated, leading to a diagnosis of AHLE following the emergence of hemorrhagic white matter lesions on repeat MRI. Remarkably, with continued treatment, the patient survived and showed gradual neurological improvement, although she remained significantly debilitated at the time of discharge. AHLE represents one of the most severe forms of demyelinating diseases, often resulting in rapid neurological decline and high mortality. This case highlights the potential link between chronic HBV infection with a high viral load and the onset of AHLE. The patient's recovery underscores the importance of early recognition and aggressive treatment in improving outcomes, even in conditions with traditionally poor prognosis. Clinicians should maintain a high index of suspicion for AHLE in patients with chronic viral infections presenting with neurological symptoms. Prompt and aggressive management can be life-saving, and ongoing research is needed to better understand the pathogenesis and optimal treatment strategies for this rare but devastating condition.

[Dengue encephalitis in Argentina]. / Encefalitis por dengue en Argentina.

Dengue virus is an endemic virus in Argentina that, although it was initially considered to be non-neurotropic, it is currently recognized to be neuroinvasive; thus conditioning a prevalence of neurological manifestations of up to 15% among patients. Even being considered severe symptoms, there is underdiagnoses of dengue encephalitis due to its varied clinical presentation. Neurological manifestations of dengue encephalitis can range from fever and headache to altered levels of consciousness and seizures. Although the cerebrospinal fluid may be normal in up to a third of cases, it usually presents increased protein concentration and pleocytosis. Regarding neuroimaging methods, the findings are usually varied and nonspecific, and can even be normal in up to 40-50% of cases. We present three cases of dengue encephalitis diagnosed in a university hospital in Buenos Aires, Argentina, where the clinical presentation varied from temporal-spatial disorientation to refractory convulsive status with different presentations in the cerebrospinal fluid but all with positive PCR for dengue in it and with normal neuroimaging.

El virus dengue es un virus endémico en Argentina que, si bien inicialmente se consideró que no era neurotrópico, actualmente se reconoce que tiene neuroinvasión, condicionando así una prevalencia de manifestaciones neurológicas de hasta el 15% entre los enfermos. Aun siendo considerados síntomas de gravedad, existe subdiagnóstico de encefalitis por dengue debido a su variada forma de presentación clínica. Las manifestaciones neurológicas de la encefalitis por dengue pueden abarcar desde fiebre y cefalea hasta alteraciones del nivel de conciencia y convulsiones. Si bien el líquido cefalorraquídeo (LCR) puede hallarse normal en hasta un tercio de los casos, lo habitual es que presente aumento de concentración de proteínas y pleocitosis. En cuanto a los métodos de neuroimagen, los hallazgos suelen ser variados e inespecíficos, e incluso pueden ser normales hasta en 40-50% de los casos. Se presentan 3 casos de encefalitis por dengue diagnosticados en un hospital universitario de Buenos Aires, Argentina, en donde la presentación clínica varió desde desorientación témporo-espacial hasta estatus convulsivo refractario con diferentes presentaciones en el LCR pero todos con PCR positivo para dengue y con neuroimágenes sin alteraciones.

Evolution from viral encephalitis to autoimmune encephalitis to multiple sclerosis: a case report.

BACKGROUND: There are established associations between viral and autoimmune encephalitis as well as between autoimmune encephalitis and demyelinating central nervous system (CNS) diseases. Here, we report the evolution from varicella zoster virus (VZV) encephalitis to limbic autoimmune encephalitis (AIE) to multiple sclerosis (MS) in one patient. CASE REPORT: A woman in her mid-thirties presented with headache, aphasia, and a generalized tonic-clonic seizure. Cerebrospinal fluid (CSF) VZV polymerase chain reaction was positive and treatment with acyclovir was administered for VZV encephalitis. Five months later, the patient presented with cognitive deficits and MRI showed new bilateral hippocampal T2-hyperintensities. CSF analyses revealed pleocytosis and neuropil antibodies in tissue-staining. A diagnosis of limbic AIE was established and treatment with IV steroids and IV immunoglobulins initiated. One year later, the patient developed paresthesia of both legs and magnetic resonance imaging studies now showed new supratentorial and spinal demyelinating lesions. The patient was diagnosed with MS and treatment was changed to rituximab. CONCLUSIONS: This unique case report links three important neuroimmunological entities in characterizing the evolution from infectious to autoimmune encephalitis to multiple sclerosis in one patient. Identification of such rare clinical constellations is critical for correct treatment choice and provides important novel insights into the pathophysiology of neuroimmunological disorders including viral triggers and overlap manifestations of autoimmune CNS diseases.

Long-term sequelae after viral meningitis and meningoencephalitis are frequent, even in mildly affected patients, a prospective observational study.

Introduction: An increasing number of studies demonstrate that viral meningitis and meningoencephalitis, even those with a mild course of meningitis, can result in residual sequelae. Methods: We aimed to investigate the long-term outcome in both viral meningitis and meningoencephalitis/encephalitis patients and impact of long-term sequelae on patients' social and professional daily lives in a prospective observational study with a follow-up period of 20 months. Results: A total of 50 patients (12% encephalitis, 58% meningoencephalitis and 30% meningitis) and 21 control persons participated in the study. The most common cause was the tick-borne encephalitis (TBE) virus. The most important persistent signs and symptoms after 2 years were subjective cognitive impairment (36%), fatigue and/or excessive daytime sleepiness (31%), disturbed nighttime sleep (31%) and headaches (13%), as well as feeling more rapidly exhausted after cognitive effort (53%). Independent of disease severity in the acute phase, almost one third of patients still reported mildly impaired social and/or professional life due to the long-term sequelae, with scores in the health status assessment still significantly lower compared to healthy controls. Discussion: Regardless of the severity of the acute illness and despite constant improvement within 2 years, 67% of patients still had persistent signs and symptoms, but these were only relevant to everyday social or professional life in about 30% of these patients.

Clinical features and prognostic model for viral encephalitis after allogeneic haematopoietic stem cell transplantation.

The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) and establish a prognostic model to identify post-transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo-HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo-HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773-0.950), and the external AUC was 0.815 (95% CI, 0.708-0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients.

Type 2 herpes simplex virus-induced anti-N-methyl-D-aspartate receptor encephalitis responsive to immunoglobulin monotherapy.

Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated.

Western equine encephalitis: a pediatric case report. / Encefalitis equina del oeste: a propósito de un caso pediátrico.

Western equine encephalitis (WEE) is a zoonotic disease caused by an RNA virus of the genus Alphavirus, and humans are accidental hosts. Although most patients do not develop symptoms upon infection, children are at higher risk for neurological involvement. Here we describe the case of a previously healthy 13-year-old male patient who lived in an urban area in the province of Buenos Aires, Argentina, who was hospitalized and diagnosed with meningoencephalitis. Due to the torpid course of his condition and because none of the most frequent microorganisms were isolated, a test for IgG antibodies for WEE virus in blood and cerebrospinal fluid was requested; both samples were positive. WEE virus is often an underdiagnosed cause of encephalitis and should be taken into consideration in both rural and urban areas.

La encefalitis equina del oeste (EEO) es una zoonosis causada por un virus ARN del género Alphavirus, del cual los humanos son huéspedes accidentales. Aunque la mayoría de los pacientes no desarrollan síntomas al infectarse, los niños tienen mayor riesgo de presentar compromiso neurológico. Presentamos el caso de un paciente de sexo masculino de 13 años de edad, previamente sano, residente de un área urbana de la provincia de Buenos Aires, Argentina, quien se internó con diagnóstico de meningoencefalitis. Por presentar evolución tórpida y, al no haber obtenido rescate microbiológico para los gérmenes más frecuentes, se solicitó la detección de anticuerpos IgG para el virus de EEO en sangre y en líquido cefalorraquídeo, ambos con resultado positivo. El virus de la EEO suele ser causa subdiagnosticada de encefalitis y debe ser considerado tanto en zonas rurales como urbanas.

An Interesting Case of Coronavirus NL63 Encephalitis Diagnosed in a 14-Year-Old Immunocompetent Female: A Case Report and Literature Review.

Human coronavirus NL63 (HCoV-NL63) belongs to the human coronavirus family but is distinct from other common coronaviruses such as HCoV-043, HCoV-229E, and SARS-CoV-1 and SARS-CoV-2 viruses. It causes a mild upper respiratory tract infection, affecting children and adults. The usual symptoms associated with the HCoV-NL63 infection are vomiting, a runny nose, and a sore throat. In vivo, HCoV-NL63 showed neurotropism as it can be detected in the CSF, through which it disseminates into the brain and the spinal column. Herein, we describe the case of a 14-year-old female patient who initially presented with disorientation and a drop in consciousness level and was admitted as a case of encephalitis to the pediatric intensive care unit.

Nipah virus-associated neuropathology in African green monkeys during acute disease and convalescence.

BACKGROUND: Nipah virus is an emerging zoonotic virus that causes severe respiratory disease and meningoencephalitis. The pathophysiology of Nipah virus meningoencephalitis is poorly understood. METHODS: We have collected the brains of African green monkeys during multiple Nipah virus, Bangladesh studies, resulting in 14 brains with Nipah virus-associated lesions. RESULTS: The lesions seen in the brain of African green monkeys infected with Nipah virus, Bangladesh were very similar to those observed in humans with Nipah virus, Malaysia infection. We observed viral RNA and antigen within neurons and endothelial cells, within encephalitis foci and in uninflamed portions of the CNS. CD8+ T cells had a consistently high prevalence in CNS lesions. We developed a UNet model for quantifying and visualizing inflammation in the brain in a high-throughput and unbiased manner. While CD8+ T cells had a consistently high prevalence in CNS lesions, the model revealed that CD68+ cells were numerically the immune cell with the highest prevalence in the CNS of NiV-infected animals. CONCLUSION: Our study provides an in-depth analysis on Nipah virus infection in the brains of primates, and similarities between lesions in patients and the animals in our study validate this model.

Serum mir-142-3p release in children with viral encephalitis and its relationship with nerve injury and inflammatory response.

BACKGROUND: Viral encephalitis (VE) is a common infectious disease of the central nervous system in children. Children with severe disease may have progressive neurological damage and even lead to death. AIMS: To assess the serum miR-142-3p levels in children with VE and the correlation between miR-142-3p and the severity and prognosis of VE. Besides, its relationship with nerve injury and inflammatory response was assessed. METHODS: Children with VE were regarded as a case group and healthy children served as control. The content of serum miR-142-3p was determined using real-time quantitative PCR. The risk factors associated with severity and prognosis of cases were evaluated using logistic analysis. The discrepancy in miR-142-3p levels, nerve injury-related indicators, and inflammatory cytokines were contrasted among groups. The ROC curve was conducted to assess the diagnostic performance of serum miR-142-3p in predicting prognosis of children with VE. RESULTS: The altered expression of miR-142-3p in serum of children with VE was enhanced in contrast to healthy control. Serum nerve injury indicators MBP, ß-EP, and NSE levels and serum inflammatory cytokines IL-6, IL-18, and IFN-γ were high in children with VE in contrast to healthy control, and had positive relevance with serum miR-142-3p. Besides, serum miR-142-3p was a risk factor associated with the severity and prognosis of children with VE. Serum miR-142-3p had diagnostic performance in predicting the prognosis of children with VE. CONCLUSION: Serum miR-142-3p content is high in children with VE and maybe a diagnosis marker for predicting prognosis. The specific miR-142-3p expression may be directly related to the severity of nerve injury and inflammatory response for VE.

Chemokine-mediated cell migration into the central nervous system in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4+ and CD8+ T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.

Differentiation between viral and autoimmune limbic encephalitis: a prospective cohort study with development and validation of a diagnostic model.

BACKGROUND: Distinguishing between viral encephalitis (VE) and autoimmune limbic encephalitis (ALE) presents a clinical challenge due to the overlap in symptoms. We aimed to develop and validate a diagnostic prediction model to differentiate VE and ALE. METHODS: A prospective observational multicentre cohort study, which continuously enrolled patients diagnosed with either ALE or VE from October 2011 to April 2023. The demographic data, clinical features, and laboratory test results were collected and subjected to logistic regression analyses. The model was displayed as a web-based nomogram and then modified into a scored prediction tool. Model performance was assessed in both derivation and external validation cohorts. RESULTS: A total of 2423 individuals were recruited, and 1001 (496 VE, 505 ALE) patients were included. Based on the derivation cohort (389 VE, 388 ALE), the model was developed with eight variables including age at onset, acuity, fever, headache, nausea/vomiting, psychiatric or memory complaints, status epilepticus, and CSF white blood cell count. The model showed good discrimination and calibration in both derivation (AUC 0.890; 0.868-0.913) and external validation (107 VE, 117 ALE, AUC 0.872; 0.827-0.917) cohorts. The scored prediction tool had a total point that ranged from - 4 to 10 also showing good discrimination and calibration in both derivation (AUC 0.885, 0.863-0.908) and external validation (AUC 0.868, 0.823-0.913) cohorts. CONCLUSIONS: The prediction model provides a reliable and user-friendly tool for differentiating between the VE and ALE, which would benefit early diagnosis and appropriate treatment and alleviate economic burdens on both patients and society.

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.

Tenascin-C in patients with central nervous system infections.

BACKGROUND: The extracellular matrix protein tenascin-C has been discovered to be an important regulator of the response to tissue injury and repair in cerebrovascular diseases. This study investigated if tenascin-C is released in response to infections in the central nervous system (CNS). METHODS: Tenascin-C concentration in the cerebrospinal fluid (CSF) was measured in patients, (>18 years) with and without CNS infections, admitted to a department of infectious diseases in Denmark. CSF tenascin-C was measured on the Meso-scale platform. RESULTS: 174 patients were included of which 140 were diagnosed with a CNS infection and 34 where this was ruled out (control group). Median CSF tenascin-C levels were significantly higher among patients with bacterial meningitis (147 pg/mL), viral meningitis (33 mg/mL), viral encephalitis (39 pg/mL) and Lyme neuroborreliosis (45 pg/mL) when compared to controls (21 pg/mL). Correlations between tenascin-C and CSF markers of inflammation and age were only moderate. CONCLUSION: Levels of CSF tenascin-C are higher among patients with bacterial and viral neuroinfections, already on admission, but exhibit only a modest correlation with baseline indices of neuroinflammation. CSF tenascin-C is highest among patients with bacterial meningitis compared to the other CNS infections. Patients with unfavorable outcomes presented with higher median CSF tenascin-C than their counterparts.

Phenotypic and transcriptional changes in peripheral blood mononuclear cells during alphavirus encephalitis in mice.

Sindbis virus (SINV) infection of mice provides a model system for studying the pathogenesis of alphaviruses that infect the central nervous system (CNS) to cause encephalomyelitis. While studies of human viral infections typically focus on accessible cells from the blood, this compartment is rarely evaluated in mice. To bridge this gap, single-cell RNA sequencing (scRNAseq) was combined with flow cytometry to characterize the transcriptional and phenotypic changes of peripheral blood mononuclear cells (PBMCs) from SINV-infected mice. Twenty-one clusters were identified by scRNAseq at 7 days after infection, with a unique cluster and overall increase in naive B cells for infected mice. Uninfected mice had fewer immature T cells and CCR9+ CD4 T cells and a unique immature T cell cluster. Gene expression was most altered in the Ki67+ CD8 T cell cluster, with chemotaxis and proliferation-related genes upregulated. Global analysis indicated metabolic changes in myeloid cells and increased expression of Ccl5 by NK cells. Phenotypes of PBMCs and cells infiltrating the CNS were analyzed by flow cytometry over 14 days after infection. In PBMCs, CD8 and Th1 CD4 T cells increased in representation, while B cells showed a transient decrease at day 5 in total, Ly6a+, and naive cells, and an increase in activated B cells. In the brain, CD8 T cells increased for the first 7 days, while Th1 CD4 T cells and naive and Ly6a+ B cells continued to accumulate for 14 days. Therefore, dynamic immune cell changes can be identified in the blood as well as the CNS during viral encephalomyelitis. IMPORTANCE: The outcome of viral encephalomyelitis is dependent on the host immune response, with clearance and resolution of infection mediated by the adaptive immune response. These processes are frequently studied in mouse models of infection, where infected tissues are examined to understand the mechanisms of clearance and recovery. However, studies of human infection typically focus on the analysis of cells from the blood, a compartment rarely examined in mice, rather than inaccessible tissue. To close this gap, we used single-cell RNA sequencing and flow cytometry to profile the transcriptomic and phenotypic changes of peripheral blood mononuclear cells (PBMCs) before and after central nervous system (CNS) infection in mice. Changes to T and B cell gene expression and cell composition occurred in PBMC and during entry into the CNS, with CCL5 being a differentially expressed chemokine. Therefore, dynamic changes occur in the blood as well as the CNS during the response of mice to virus infection, which will inform the analysis of human studies.