-
Journal of Virus Eradication Mar 2024West Nile virus (WNV) is an important neurotropic virus that accounts for the emergence of human arboviral encephalitis and meningitis. The interaction of WNV with...
West Nile virus (WNV) is an important neurotropic virus that accounts for the emergence of human arboviral encephalitis and meningitis. The interaction of WNV with signaling pathways plays a key role in controlling WNV infection. We have investigated the roles of the AKT and ERK pathways in supporting WNV propagation and modulating the inflammatory response following WNV infection. WNV established a productive infection in neuronal cell lines originated from human and mouse. Expression of IL-11 and TNF-α was markedly up-regulated in the infected human neuronal cells, indicating elicitation of inflammation response upon WNV infection. WNV incubation rapidly activated signaling cascades of AKT (AKT-S6-4E-BP1) and ERK (MEK-ERK-p90RSK) pathways. Treatment with AKT inhibitor MK-2206 or MEK inhibitor U0126 abrogated WNV-induced AKT or ERK activation. Strong activation of AKT and ERK signaling pathways could be detectable at 24 h after WNV infection, while such activation was abolished at 48 h post infection. U0126 treatment or knockdown of ERK expression significantly increased WNV RNA levels and viral titers and efficiently decreased IL-11 production induced by WNV, suggesting the involvement of ERK pathway in WNV propagation and IL-11 induction. MK-2206 treatment enhanced WNV RNA replication accompanied with a moderate decrease in IL-11 production. These results demonstrate that engagement of AKT and ERK signaling pathways facilitates viral infection and may be implicated in WNV pathogenesis.
PubMed: 38601702
DOI: 10.1016/j.jve.2024.100368 -
Immunity May 2024Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How...
Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11cCD80 cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
Topics: Animals; Interferon Type I; Lymphocytic Choriomeningitis; Mice; Lymphocytic choriomeningitis virus; Memory B Cells; Epigenesis, Genetic; Mice, Inbred C57BL; Receptor, Interferon alpha-beta; Immunologic Memory; Chronic Disease; B-Lymphocyte Subsets; Single-Cell Analysis
PubMed: 38593796
DOI: 10.1016/j.immuni.2024.03.016 -
Cureus Mar 2024Cryptococcal meningitis should be considered in individuals diagnosed with human immunodeficiency virus (HIV) infection and presenting with a cluster of differentiation...
Cryptococcal meningitis should be considered in individuals diagnosed with human immunodeficiency virus (HIV) infection and presenting with a cluster of differentiation 4 (CD4)-helper T cell count below 100 cells/ml. The 2022 guidelines from the World Health Organization (WHO) advocate for initiating treatment with a high dose (10 mg/kg) of liposomal amphotericin B, followed by flucytosine and fluconazole for a two-week duration. Additionally, alternative treatment options involving a combination of flucytosine and fluconazole are recommended. Consolidation therapy, as per the WHO guidelines, involves an eight-week course of fluconazole (800 mg), initiated after the induction phase. The dosage is then reduced to 200 mg/day, maintaining this level until the CD4 count exceeds 200 cells/mm. Notably, the 2022 WHO guidelines prioritize a single dose of liposomal amphotericin B (LampB) over amphotericin B deoxycholate (AmpB-D) at 1 mg/kg due to its association with fewer side effects, including decreased mortality, kidney damage, and anemia. These recommendations are founded on the outcomes of the Ambisome Therapy Induction Optimization (AMBITION-CM), a multicenter, open-label, randomized controlled trial. This case report details the outpatient management of cryptococcal meningitis in a 47-year-old male with acquired immunodeficiency syndrome (AIDS) who exhibited intolerance to fluconazole. In this scenario, the decision to employ liposomal amphotericin B (LampB) as the sole agent for treatment during the outpatient phase was driven by challenges in tolerating fluconazole. Despite the absence of specific research on LampB's standalone use during the maintenance and consolidation phases, concerns regarding the patient's adverse reaction to fluconazole influenced the choice. Notably, LampB's once-weekly infusion schedule, although more expensive than AmpB-D, contributes to enhanced patient compliance. Exploring alternatives to traditional medications, such as interferon-gamma (INF-γ), Mycograb, 18B7, APX001, and T2307, holds promise in targeting novel antigens or complementing existing treatment regimens. Post-discharge, the patient received weekly LampB infusions alongside antiretroviral therapy (ART), resulting in an undetectable viral load and an increased CD4 count. A subsequent cerebrospinal fluid analysis post-discharge revealed a positive India ink stain but negative cultures for Cryptococcus, underscoring the necessity for a comprehensive and adaptable approach in managing cryptococcal meningitis.
PubMed: 38590504
DOI: 10.7759/cureus.55824 -
CNS Drugs May 2024Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have... (Review)
Review
Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system. Neurotropic viruses may then enter the intracellular space of brain cells via endocytosis and/or membrane fusion. Antiviral drugs are currently used for different viral CNS infections, even though their use and dosing regimens within the CNS, with the exception of acyclovir, are minimally supported by clinical evidence. We therefore provide considerations to optimize drug treatment(s) for these neurotropic viruses. Antiviral drugs should cross the blood-brain barrier/blood cerebrospinal fluid barrier and pass the brain cellular membrane to inhibit these viruses inside the brain cells. Some antiviral drugs may also require intracellular conversion into their active metabolite(s). This illustrates the need to better understand these mechanisms because these processes dictate drug exposure within the CNS that ultimately determine the success of antiviral drugs for CNS infections. Finally, we discuss mathematical model-based approaches for optimizing antiviral treatments. Thereby emphasizing the potential of CNS physiologically based pharmacokinetic models because direct measurement of brain intracellular exposure in living humans faces ethical restrictions. Existing physiologically based pharmacokinetic models combined with in vitro pharmacokinetic/pharmacodynamic information can be used to predict drug exposure and evaluate efficacy of antiviral drugs within the CNS, to ultimately optimize the treatments of CNS viral infections.
Topics: Humans; Central Nervous System Viral Diseases; Viruses; Central Nervous System; Brain; Blood-Brain Barrier; Antiviral Agents
PubMed: 38580795
DOI: 10.1007/s40263-024-01082-3 -
Cureus Mar 2024Nonsteroidal anti-inflammatory drug (NSAID)-induced aseptic meningitis (NIAM) is frequently reported in patients with autoimmune disease. Ibuprofen-induced NIAM is the...
Nonsteroidal anti-inflammatory drug (NSAID)-induced aseptic meningitis (NIAM) is frequently reported in patients with autoimmune disease. Ibuprofen-induced NIAM is the most common case report of NIAM. We report a patient without autoimmune disease who developed NIAM following oral celecoxib administration. A literature review and survey of cases registered in the Japanese Adverse Drug Event Report (JADER) database is also provided. A 73-year-old woman with no autoimmune disease developed a headache the day after taking celecoxib, and NIAM was suspected. The headache resolved quickly following celecoxib discontinuation. Although lumbar puncture was not available in this case, bacterial or viral meningitis was negative, and NIAM could not be ruled out. This case involved an older adult patient without an autoimmune disease, with celecoxib as the causative NSAID. A literature review found numerous cases of autoimmune diseases in younger patients. To date, only one case of celecoxib-induced NIAM has been reported. Analysis of NIAM cases in JADER revealed an onset time of approximately three days. JADER analysis indicated that NIAM tended to occur immediately after administration, although the onset with cyclooxygenase-2 selective agents might be slower.
PubMed: 38559550
DOI: 10.7759/cureus.55348 -
Magnetic Resonance Imaging Clinics of... May 2024Spinal infections are a diverse group of diseases affecting different compartments of the spine with variable clinical and imaging presentations. Diagnosis of spinal... (Review)
Review
Spinal infections are a diverse group of diseases affecting different compartments of the spine with variable clinical and imaging presentations. Diagnosis of spinal infections is based on a combination of clinical features, laboratory markers, and imaging studies. Imaging plays a pivotal role in the diagnosis and management of spinal infections. The characteristic imaging manifestations of bacterial and viral infections in the spine are discussed with key teaching points emphasized.
Topics: Humans; Spondylitis; Magnetic Resonance Imaging; Spine; Virus Diseases; Communicable Diseases; Discitis
PubMed: 38555143
DOI: 10.1016/j.mric.2023.12.003 -
Magnetic Resonance Imaging Clinics of... May 2024Diagnosis of brain infections is based on a combination of clinical features, laboratory markers, and imaging findings. Imaging characterizes the extent and severity of... (Review)
Review
Diagnosis of brain infections is based on a combination of clinical features, laboratory markers, and imaging findings. Imaging characterizes the extent and severity of the disease, aids in guiding diagnostic and therapeutic procedures, monitors response to treatment, and demonstrates complications. This review highlights the characteristic imaging manifestations of bacterial and viral infections in the brain.
Topics: Humans; Magnetic Resonance Imaging; Prions; Brain; Communicable Diseases
PubMed: 38555142
DOI: 10.1016/j.mric.2023.11.001 -
The Journal of Infection May 2024The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial...
OBJECTIVES
The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.
METHODS
Children aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology.
RESULTS
The cohort included 3002 children (median age 2·4 months); 1101/3002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged <6 months and 10-16 years, with Neisseria meningitidis and/or Streptococcus pneumoniae commonest at age 6 months to 9 years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after lumbar puncture (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis.
CONCLUSIONS
Bacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis.
FUNDING
This study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research.
Topics: Humans; Child; Infant; Meningitis, Bacterial; Child, Preschool; Adolescent; Female; Male; Prospective Studies; Vaccines, Conjugate; Meningitis, Viral; Clinical Decision Rules; United Kingdom; Neisseria meningitidis; Streptococcus pneumoniae; Decision Support Techniques
PubMed: 38552719
DOI: 10.1016/j.jinf.2024.106145 -
Emerging Microbes & Infections Dec 2024Coxsackievirus B4 (CVB4) is associated with a range of acute and chronic diseases such as hand, foot, and mouth disease, myocarditis, meningitis, pancreatitis, and type...
Coxsackievirus B4 (CVB4) is associated with a range of acute and chronic diseases such as hand, foot, and mouth disease, myocarditis, meningitis, pancreatitis, and type 1 diabetes, affecting millions of young children annually around the world. However, no vaccine is currently available for preventing CVB4 infection. Here, we report the development of inactivated viral particle vaccines for CVB4. Two types of inactivated CVB4 particles were prepared from CVB4-infected cell cultures as vaccine antigens, including F-particle (also called mature virion) consisting of VP1, VP3, VP2, and VP4 subunit proteins, and E-particle (also called empty capsid) which is made of VP1, VP3, and uncleaved VP0. Both the inactivated CVB4 F-particle and E-particle were able to potently elicit neutralizing antibodies in mice, despite slightly lower neutralizing antibody titres seen with the E-particle vaccine after the third immunization. Importantly, we demonstrated that passive transfer of either anti-F-particle or anti-E-particle sera could completely protect the recipient mice from lethal CVB4 challenge. Our study not only defines the immunogenicity and protective efficacy of inactivated CVB4 F-particle and E-particle but also reveals the central role of neutralizing antibodies in anti-CVB4 protective immunity, thus providing important information that may accelerate the development of inactivated CVB4 vaccines.
Topics: Humans; Child; Animals; Mice; Child, Preschool; Antibodies, Viral; Antibodies, Neutralizing; Immunization; Vaccination; Vaccines; Viral Vaccines
PubMed: 38551145
DOI: 10.1080/22221751.2024.2337665 -
Vaccine Apr 2024The introduction of varicella vaccines into routine pediatric immunization programs has led to a considerable reduction in varicella incidence. However, there have been...
BACKGROUND
The introduction of varicella vaccines into routine pediatric immunization programs has led to a considerable reduction in varicella incidence. However, there have been reports of varicella, herpes zoster, and meningitis caused by the vaccine strain of varicella-zoster virus (VZV), raising concerns. Establishing the relationship between the wild-type and vaccine strains in VZV infections among previously vaccinated individuals is crucial. Differences in the single nucleotide polymorphisms (SNPs) among vaccine strains can be utilized to identify the strain. In this study, we employed nanopore sequencing to identify VZV strains and analyzed clinical samples.
METHODS
We retrospectively examined vesicle and cerebrospinal fluid samples from patients with VZV infections. One sample each of the wild-type and vaccine strains, previously identified using allelic discrimination real-time PCR and direct sequencing, served as controls. Ten samples with undetermined VZV strains were included. After DNA extraction, a long PCR targeting the VZV ORF62 region was executed. Nanopore sequencing identified SNPs, allowing discrimination between the vaccine and wild-type strains.
RESULTS
Nanopore sequencing confirmed SNPs at previously reported sites (105,705, 106,262, 107,136, and 107,252), aiding in distinguishing between wild-type and vaccine strains. Among the ten unknown samples, nine were characterized as wild strains and one as a vaccine strain. Even in samples with low VZV DNA levels, nanopore sequencing was effective in strain identification.
CONCLUSION
This study validates that nanopore sequencing is a reliable method for differentiating between the wild-type and vaccine strains of VZV. Its ability to produce long-read sequences is remarkable, allowing simultaneous confirmation of known SNPs and the detection of new mutations. Nanopore sequencing can serve as a valuable tool for the swift and precise identification of wild-type and vaccine strains and has potential applications in future VZV surveillance.
Topics: Humans; Child; Herpesvirus 3, Human; Chickenpox; Nanopore Sequencing; Retrospective Studies; Polymorphism, Restriction Fragment Length; Polymerase Chain Reaction; Chickenpox Vaccine; Herpes Zoster; DNA, Viral
PubMed: 38548526
DOI: 10.1016/j.vaccine.2024.03.046