Search Results (129)

Mumps virus (MuV) is a single-stranded, negative-sense RNA virus of the Family Paramyxoviridae. MuV is a highly contagious human pathogen that causes primarily mild symptoms, including hallmark swelling of the parotid glands. Severe cases can occur, leading to neurological complications, including deafness, meningitis, and encephalitis. The mumps vaccine, now included in combination with measles and rubella vaccines (MMR), was first made available in the 1960s. After its introduction, mumps incidence dropped dramatically to less than 500 cases annually in the US. However, even with long-standing vaccination programs, MuV continues to challenge the landscape of public health due to a resurgence of cases in the past several decades and a still present lack of approved antiviral drugs and treatments available for the disease. This review will explore the biology of MuV, focusing on how MuV replicates and interacts with the host immune system. Recent studies have also shed light on the role of protein phosphorylation in regulating viral RNA synthesis—particularly the dynamic interactions between the nucleoprotein (NP) and phosphoprotein (P)—offering new insights into how the virus controls its replication machinery both mechanistically and through utilizing host cell advantages. We also examine how the immune system responds to mumps infection and vaccination, and how those responses may vary across viral genotypes. Although the Jeryl Lynn vaccine strain has played a key role in controlling mumps for decades, outbreaks among vaccinated individuals have raised questions about the present vaccine’s efficacy against circulating and emerging genotypes and if novel strategies will be required to prevent future outbreaks. We review current epidemiological data, highlighting shifts in MuV transmission and genotype distribution, and discuss the need for updated or genotype-matched vaccines. By connecting molecular virology with real-world trends in disease spread and vaccine performance, this review aims to support ongoing efforts to strengthen mumps control strategies and inform the development of next-generation vaccines. Full article

Background/Objectives: Polymerase chain reaction (PCR) testing of ocular fluids is an essential diagnostic method for identifying infectious causes of uveitis. However, multiplex PCR kits specifically developed for ophthalmic use are not commercially available in many regions, including Korea. Given the biochemical similarity between cerebrospinal fluid (CSF) and aqueous humor, this study evaluated the diagnostic utility of a commercially available CSF multiplex PCR panel for detecting herpesviruses in patients with suspected viral uveitis. Methods: We retrospectively reviewed the medical records of patients whose aqueous humor samples were analyzed using a multiplex PCR assay originally designed for CSF testing (Seeplex Meningitis-V1 ACE Detection kit, Seegene, Seoul, Republic of Korea). The samples were obtained between May 2019 and June 2023 at two tertiary referral hospitals. The assay targeted herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and human herpesvirus 6 (HHV-6). Patients were classified into three groups: (I) anterior uveitis with suspected herpesviral infection, (II) acute retinal necrosis (ARN), and (III) CMV retinitis. Baseline characteristics, PCR positivity rates, and virus prevalence were compared among the groups. Results: Among 149 eyes tested, 86 were included in the final analysis. The overall positivity rate was 38.4%. PCR positivity was 19.7% (12/61) in Group I, 93.8% (15/16) in Group II, and 66.7% (6/9) in Group III. CMV was the most common pathogen in Groups I (66.7%) and III (100%), while VZV was predominant in Group II (80%). No HHV-6 infection was detected. Conclusions: The positivity rate in anterior uveitis (Group I) was lower than previously reported, likely due to the limited sample volume relative to the assay’s requirement. Nevertheless, the assay demonstrated diagnostic reliability comparable to previous reports for ARN and CMV retinitis. Therefore, the CSF-based multiplex PCR panel serves as a feasible and cost-effective diagnostic option for sight-threatening posterior segment infections, facilitating prompt diagnosis and treatment, although further optimization is warranted for anterior uveitis. Full article

Epstein-Barr virus (EBV) infection shows the strongest causative association with multiple sclerosis (MS), but its contribution to disease progression and the mechanisms allowing for viral persistence in the MS brain are still elusive. Studies in post-mortem MS brain tissue indicate an ongoing yet ineffective antiviral immune reaction in advanced stages of the disease. EBV has evolved strategies to evade immune recognition and clearance by the host immune system during both the latency and lytic phase of its life cycle. Recent evidence demonstrates that cells expressing EBV latent membrane protein (LMP) 2A exploit the PD-1/PDL1 inhibitory immune checkpoint to escape immune surveillance and maintain a persistent latent infection in the MS brain. This study investigated whether the virus also utilizes this inhibitory mechanism during other phases of the viral life cycle. By using multiple immunostainings on highly inflamed MS brain tissues containing meningeal tertiary lymphoid structures (TLSs), we analyzed PD-L1 expression on EBV-infected cells expressing EBNA2, five EBV lytic gene products, BZLF1, BHRF1, BMRF1, BALF2, and gp350/220, as well as on follicular dendritic cells within the TLSs. This is the first study describing in secondary progressive MS brain tissue the expression and the cellular and tissue distribution of PD-L1 on EBV-infected cells being in different stages of the viral life cycle, and confirms the meningeal TLSs as immune-permissive habitats favoring the maintenance of an intracerebral EBV reservoir. Full article

Background/Objectives: Central nervous system (CNS) infections remain a significant public health challenge and require rapid and accurate diagnosis to guide clinical management. Although the incidence of bacterial meningitis has declined owing to widespread vaccination, viral etiologies continue to dominate CNS infections. The aim of this study was to assess the epidemiological trends, age distribution, and seasonality of CNS infections using multiplex PCR. Methods: A retrospective analysis was conducted on cerebrospinal fluid (CSF) samples collected between January 2021 and December 2022 from patients with CNS infections at King Abdulaziz Medical City. A BioFire FilmArray Meningitis/Encephalitis (ME) panel was used to detect pathogens. Patient demographics, pathogen distribution, and seasonal trends were analyzed. Results: A total of 2460 CSF samples were tested, of which 130 (5%) were positive for at least one pathogen. Viral pathogens accounted for 82.3% of the infections, with human herpesvirus-6 (HHV-6) (31%) and enterovirus (EV) (20%) being the most common. Bacterial pathogens represented 17.7% of the cases, with Streptococcus pneumoniae (6%) and Escherichia coli K1 (5%) being the predominant bacterial agents. The highest infection burden was observed in infants aged 0–6 months, with a marked male predominance. Seasonal analysis revealed multiple peaks in viral infections, particularly of HHV-6 and EVs, whereas bacterial infections were sporadic, with Streptococcus agalactiae and Streptococcus pneumoniae peaking in October and November. Conclusions: Viral infections, particularly HHV-6 and EVs, dominated CNS infections, with distinct seasonal and age-related variations. These findings underscore the value of multiplex PCR in improving the rapid diagnosis of CNS infections and aiding in timely treatment and antimicrobial stewardship. Full article

Background/Objectives: Meningoencephalitis (ME) is a life-threatening infectious disease; therefore, prompt and accurate diagnosis is lifesaving. Traditional diagnostic methods, such as culture, have several limitations related to sensitivity and specificity. Emerging multiplex ME-PCR panels are a comprehensive and rapid tool in a single test. The Bio-Speedy Meningitis/Encephalitis RT-qPCR MX-17 panel (Bioeksen R&D Technologies Inc., Turkey) enables testing for 17 targets. To evaluate the performance of the panel compared to clinical and CSF parameters. Methods: A total of 403 patients with a preliminary diagnosis of ME were reviewed between January 2019 and September 2023. Following revision, 72 patients with clinical, CSF, and laboratory findings were included. The tested panel was used to detect targeted pathogens in CSF samples. The 30-day survival rate and prolonged stay were analyzed. Results: The median CSF protein value was 59.5 mg/dL (14.2–1471 mg/dL) and glucose was 61.95 mg/dL (0.083–165 mg/dL). Forty-one (56.9%) ME panel results were positive, among which 38.9% (28) were viral and 19.4% (14) were bacterial. HHV-6 ranked first with a rate of 15.3%. The Bio-Speedy panel test results outperformed the CSF culture (p < 0.001). The correlation of the Bio-Speedy panel with impaired consciousness was statistically significant (p = 0.004). Six (8.3%) patients from the study group died within 30 days. Conclusions: Compared to traditional methods, Bio-Speedy panel was effective in identifying the causative agents of ME. The Bio-Speedy ME RT-qPCR MX-17 panel offers accurate detection of ME-causing pathogens. The implementation of the panel in clinical practice can impact patient management and improve outcomes. Full article

Enteroviruses, a diverse genus within the Picornaviridae family, are responsible for a wide range of human infections, including hand, foot, and mouth disease, respiratory disease, aseptic meningitis, encephalitis, myocarditis, and acute flaccid paralysis. Despite their substantial global health burden and the frequent emergence of outbreaks, no specific antiviral therapies are currently approved for clinical use against non-polio enteroviruses. This review provides a comprehensive overview of the current landscape of antiviral strategies targeting enteroviruses, including direct-acting antivirals such as capsid binders, protease inhibitors, and viral RNA polymerase inhibitors. We also examine the potential of host-targeting agents that interfere with virus–host interactions essential for replication. Emerging strategies such as immunotherapeutic approaches, RNA interference, CRISPR-based antivirals, and peptide-based antivirals are also explored. Furthermore, we address key challenges, including viral diversity, drug resistance, and limitations in preclinical models. By highlighting recent advances and ongoing efforts in antiviral development, this review aims to guide future research and accelerate the discovery of effective therapies against enterovirus infections. Full article

Enterovirus A71 (EVA71) is a major pathogen that causes hand, foot, and mouth disease (HFMD). Although the symptoms of HFMD can be self-limiting, severe meningitis, encephalitis, myocarditis, and acute flaccid paralysis may occur. Upon EVA71 infection, the host cells deploy an intricate network of factors to orchestrate cellular responses and maintain cellular homeostasis. However, the virus has evolved various strategies to avoid unfavorable host restrictions and to establish a productive infection process. As response regimens are correlated with disease symptoms, exploring the interactions between the virus and host contributes to understanding the pathogenesis and underlying mechanisms of infection. In this review, we summarized the recent research progress related to pro-viral factors during EVA71 infection and discussed the underlying mechanisms employed by EVA71 to facilitate virion production. These insights may help identify antiviral therapeutic candidates and support vaccine development. Full article

Background: Etiologic diagnosis in suspected viral meningitis is not always achievable, yet it can play a significant role in patient management. Our study aimed to do a comprehensive analysis of current practices regarding etiologic diagnosis in these cases and compare patients with and without known etiologic diagnosis in order to visualize if and how having an etiological diagnosis can impact patient management and/or outcome. Methods and results: We conducted a convergent mixed-methods study. Quantitative data was obtained from 118 patients hospitalized during a one-year period. There were 40.7% (n = 48) cases with unknown etiology. The length of hospitalization was longer in the group with unknown etiology vs. known etiology (12.6 days vs. 9.8 days p = 0.01). Thematic analysis was used for the qualitative approach in order to evaluate physicians’ overall perceptions regarding this subject. Conclusions: Our mixed-methods study shows that while clinicians consider etiologic diagnosis very important, it remains a diagnostic challenge even in modern times. Continued efforts are needed to optimize diagnostic strategies and address existing gaps in the etiologic workup of viral meningitis. There may be overlooked pathogens that have cost-efficient testing methods, like TBEV, that can be introduced in a testing protocol and may enhance patient management and reduce unnecessary hospital stays. Full article

Coxsackievirus B3 (CV-B3) infection causes inflammatory conditions such as viral myocarditis and meningitis, and incidence rates are rising annually. While children are more likely to be affected by severe manifestations, the molecular basis of this age-dependent susceptibility is poorly understood. In this study, we used young Balb/c mice at three developmental stages (7-, 14-, and 30-day-old mice) to investigate CV-B3 pathogenesis. Our findings revealed that 7-day-old mice exhibited substantial infection susceptibility and pathological severity compared to older mice. Critically, an age-dependent analysis showed a progressive decline in the expression of CV-B3-binding Coxsackievirus and Adenovirus Receptor (CAR) splice variants (CAR1 and CAR2) at both the transcriptional and translational levels as the mice matured from 7 to 30 days. These receptor isoforms demonstrated a direct correlation with viral replication efficiency in younger hosts. Concurrently, aging was associated with a rise in non-binding CAR variants (CAR3 and CAR4). During CV-B3 infection, the abundance of CAR1/CAR2 in young mice facilitated accelerated viral proliferation, coupled with the hyperactivation of the NLRP3 inflammasome and the expansion of IL-17-producing γδT cells (γδT17 cells). This cascade triggered excessive production of proinflammatory cytokines (IL-1β, IL-18, and IL-17), culminating in pronounced inflammatory infiltrates within cardiac and cerebral tissues. These findings establish NLRP3 inflammasome dysregulation as a critical determinant of CV-B3-induced tissue damage and provide novel insights into the heightened susceptibility to CV-B infection during early life and its associated severe disease rates. Full article

Echovirus 18, a member of the B group of enteroviruses, is a significant etiological agent of aseptic meningitis and viral encephalitis in children. In this study, we investigated the pathogenicity of E18 by establishing a mouse infection model after comparing various mouse strains and injection methods. Two-day-old IFNAR1 knockout mice infected with clinical isolates of E18 exhibited symptoms such as lethargy, hind limb paralysis, and even mortality. Similarly, some two-day-old C57BL/6J mice displayed comparable symptoms; however, the incidence was lower than that observed in IFNAR1 knockout mice. No similar symptoms were noted in any Balb/c mice. Significant pathological changes were observed in skeletal muscle, brain tissue, and other organs of symptomatic mice; among these tissues, skeletal muscle demonstrated the highest viral load. The established infection model using two-day-old IFNAR1 knockout mice provides valuable insights into further investigations regarding its pathological injury mechanisms as well as the protective effects conferred by antibodies. Full article

While viral pathogens are often subdivided into neurotropic and non-neurotropic categories, systemic inflammation caused by non-neurotropic viruses still possesses the ability to alter the central nervous system (CNS). Studies of CNS disease induced by viral infection, whether neurotropic or not, are presented with a unique set of challenges. First, because brain biopsies are rarely necessary to diagnose viral-associated neurological disorders, antemortem tissue samples are not readily available for study and human pathological studies must rely on end-stage, postmortem evaluations. Second, in vitro models fail to fully capture the nuances of an intact immune system, necessitating the use of animal models to fully characterize pathogenesis and identify potential therapeutic approaches. Non-human primates (NHP) represent a particularly attractive animal model in that they overcome many of the limits posed by more distant species and most closely mirror human disease pathogenesis and susceptibility. Here, we review NHP infection models of viruses known to infect and/or replicate within cells of the CNS, including West Nile virus, the equine encephalitis viruses, Zika virus, and herpesviruses, as well as those known to alter the immune status of the brain in the absence of significant CNS penetrance, including human immunodeficiency virus (HIV) in the current era of combination antiretroviral therapy (cART) and the coronavirus of severe acute respiratory syndrome (SARS)-CoV−2. This review focuses on viruses with an established role in causing CNS disease, including encephalitis, meningitis, and myelitis and NHP models of viral infection that are directly translatable to the human condition through relevant routes of infection, comparable disease pathogenesis, and responses to therapeutic intervention. Full article

Viral infections may vary from mild to severe, manifesting with a wide range of symptoms, including skin lesions, influenza-like symptoms, or meningitis/meningoencephalitis signs. Viruses that cause both skin lesions and meningitis comprise, e.g., Enteroviruses (EVs) and Herpes viruses (HV). EVs are responsible for approximately 90% of viral meningitis cases. They occur frequently among children under 3 years of age and are characterized by various types of rash. HV infections are responsible for up to 18% of viral meningitis, mostly among adults or older children. Most patients with viral meningitis recover entirely. However, the rates of serious complications and mortality may be as high as 74% and 10%, respectively, for particularly vulnerable neonatal or immunocompromised patients. Patients that present signs of encephalitis and/or are suspected to have HSV/VZV infection require immediate implementation of empiric acyclovir therapy before receiving the polymerase chain reaction (PCR) test results. The clinical picture of viral meningitis may differ depending on the virus, including the presence of both meningeal signs and skin lesions. Therefore, early identification of the etiological factor is necessary for early and proper treatment implementation. It is crucial to accurately differentiate between the causative agents, and this work focuses on answering the question of how skin lesions can assist in achieving a better and faster diagnosis. The aim of this review was to analyze the characteristics of skin lesions in the course of meningitis caused by various viral species. This can be helpful for physicians in the diagnostic process and subsequent treatment. Full article

In the first 90 days, most meningitis cases are viral. Newborns often show nonspecific symptoms, making early diagnosis difficult but crucial for effective treatment and good outcomes. Cerebro-spinal fluid (CSF) analysis is the gold standard for diagnosis, enabling targeted therapy. We report on a newborn with rare viral meningitis due to herpes simplex virus type 1 and enterovirus coinfection. This uncommon situation complicates diagnostic and therapeutic management. We share our experience and review the limited literature on such neonatal viral coinfections. Full article

Case summary: A 2-year-old male neutered domestic shorthair cat was presented with a progressive history of tetraparesis, ataxia, and inappetence over 4 days. A physical exam revealed mucopurulent nasal discharge and stertor. A neurologic exam revealed a multifocal neurolocalization. The cat was non-ambulatory tetraparetic and developed seizures while in hospital. Hematologic assessment revealed anemia, hypoalbuminemia and hyperglobulinemia. Magnetic resonance imaging (MRI) of the brain revealed multifocal meningeal contrast enhancement in the brainstem and cervical spine, as well as mandibular and retropharyngeal lymphadenopathy. Cerebrospinal fluid revealed marked neutrophilic pleocytosis; no infectious organisms were seen. Toxoplasma IgG/IgM and Cryptococcus antigen latex agglutination were negative. Mandibular and abdominal lymph nodes were aspirated, and cytology revealed mixed inflammation. The cat was suspected to have feline infectious peritonitis, and to aid in clinical diagnosis he was enrolled in research study—with targeted Nanopore-based sequencing specifically identifying and characterizing FCoV-1 RNA in spinal fluid and anal swab, but not in urine. The cat was treated with anticonvulsants (phenobarbital and levetiracetam), an antibiotic (ampicillin/clavulanic acid), and GS-441524. Neurologic signs did not improve on an antibiotic alone but improved significantly after two subcutaneous injections of GS-441524. The cat received an 84-day course of GS-441524 and, at the time of manuscript preparation (over 12 months after diagnosis), remains ambulatory and seizure-free without recurrence of neurologic signs and no detectable viral shedding in feces. Full article

Acute central nervous system (CNS) infections, such as meningitis and encephalitis, represent medical emergencies that require rapid identification of the causative pathogen to guide appropriate therapeutic interventions. The QIAstat-Dx^® Meningitis/Encephalitis (QIA/ME) is a molecular syndromic panel that enables the simultaneous detection of multiple pathogens and provides the visualization of cycle threshold (Ct) values, offering rapid results for prompt clinical management. This study retrospectively tested, with the QIA/ME panel, 170 cerebrospinal fluid (CSF) samples from patients with CNS infections, confirmed through routine diagnostic workflows. The results were compared with those obtained from bacterial culture and singleplex PCR for viral detection. The QIA/ME demonstrated 100% concordance with reference methods for bacterial and yeast infections. For viral infections, the overall detection rate was 85.9%. Specifically, when singleplex PCR results exceeded 250 copies/mL for DNA viruses and 500 copies/mL for the RNA virus, the concordance rate with the QIA/ME was 96.8%. In contrast, when PCR values were below these thresholds, the concordance rate dropped to 43.8%. A strong overall correlation was observed between the viral load measured by singleplex PCR and Ct values from the QIA/ME (ρ = −0.83, p < 0.001). Only for enterovirus a weak correlation was found (ρ = −0.40, p = 0.056). The QIA/ME panel is an effective diagnostic tool for viral CNS infections, allowing for the visualization of Ct values that reflect pathogen load in samples and which could be useful in guiding clinical decision-making and patient management. Full article