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Viruses Jan 2024Japanese encephalitis virus (JEV) belongs to the family and is a representative mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans.... (Review)
Review
Japanese encephalitis virus (JEV) belongs to the family and is a representative mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. Despite the availability of vaccines, JEV remains a major public health threat with the potential to spread globally. According to the World Health Organization (WHO), there are an estimated 69,000 cases of JE each year, and this figure is probably an underestimate. The majority of JE victims are children in endemic areas, and almost half of the surviving patients have motor or cognitive sequelae. Thus, the absence of a clinically approved drug for the treatment of JE defines an urgent medical need. Recently, several promising and potential drug candidates were reported through drug repurposing studies, high-throughput drug library screening, and de novo design. This review focuses on the historical aspects of JEV, the biology of JEV replication, targets for therapeutic strategies, a target product profile, and drug development initiatives.
Topics: Child; Animals; Humans; Encephalitis Virus, Japanese; Encephalitis, Japanese; Encephalitis, Viral; High-Throughput Screening Assays; Drug Development
PubMed: 38399978
DOI: 10.3390/v16020202 -
Viruses Jan 2024Enteroviruses (EVs) represent a major cause of viral meningitis, being responsible for nearly 1 billion infections each year worldwide. Several techniques were developed...
Enteroviruses (EVs) represent a major cause of viral meningitis, being responsible for nearly 1 billion infections each year worldwide. Several techniques were developed to obtain better diagnostic results of EV infections. Herein, we evaluated the efficiency of EV detection through isolation on both Rhabdomyosarcoma (RD) and Vero cell line cultures, conventional reverse transcription-polymerase chain reaction (RT-PCR) and real-time RT-PCR. Thus, 50 cerebrospinal fluid (CSF) samples belonging to patients suspected to have viral meningitis in northern Algeria were collected, anonymously numbered from 1 to 50 and subjected to the above-mentioned techniques for EV detection. Using real-time RT-PCR, 34 CSF samples were revealed to be positive for viral origin of meningitis (68%). Thirteen of them were positive when the conventional RT-PCR was used (26%), and only three samples gave positive results when the cell culture technique was used (6%). Surprisingly, two cell culture-positive CSF samples, namely, 31 and 39, were negative using RT-PCR directly on the original samples. However, they turned to be positive when amplification was carried out on their corresponding cell culture supernatant. The cell-cultured viral isolates were then identified by sequencing their viral genome's VP1 regions. All of them were revealed to belong to the echovirus 27 strain. This investigation demonstrates that RT-PCR techniques are often more sensitive, accurate and much faster, providing reliable results within a clinically acceptable timeframe. However, viral isolation on cell cultures remains crucial to obtain enough viral load for serological tests or even to avoid the rare, but existing, false negative PCR.
Topics: Animals; Chlorocebus aethiops; Humans; RNA, Viral; Enterovirus; Enterovirus Infections; Meningitis, Viral; Vero Cells; Antigens, Viral; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 38399946
DOI: 10.3390/v16020170 -
Fluids and Barriers of the CNS Feb 2024Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic...
BACKGROUND
Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH), and infection (meningitis) promote pro-inflammatory CSF conditions reflected in CSF parameters.
METHODS
Biochemical and cytological profiles of lumbar CSF and peripheral blood samples were analyzed for 81 control, 29 IVH grade 1/2 (IVH), 13 IVH grade 3/4 (IVH), 15 PHH, 20 culture-confirmed bacterial meningitis (BM), and 27 viral meningitis (VM) infants at 36.5 ± 4 weeks estimated gestational age.
RESULTS
PHH infants had higher (p < 0.02) CSF total cell and red blood cell (RBC) counts compared to control, IVH, BM, and VM infants. No differences in white blood cell (WBC) count were found between IVH, PHH, BM, and VM infants. CSF neutrophil counts increased (p ≤ 0.03) for all groups compared to controls except IVH. CSF protein levels were higher (p ≤ 0.02) and CSF glucose levels were lower (p ≤ 0.003) for PHH infants compared to all other groups. In peripheral blood, PHH infants had higher (p ≤ 0.001) WBC counts and lower (p ≤ 0.03) hemoglobin and hematocrit than all groups except for IVH.
CONCLUSIONS
Similarities in CSF parameters may reflect common pathological processes in the inflammatory response and show the complexity associated with interpreting CSF profiles, especially in PHH and meningitis/ventriculitis.
Topics: Infant; Infant, Newborn; Humans; Infant, Premature; Clinical Relevance; Cerebral Hemorrhage; Hydrocephalus; Central Nervous System Infections; Meningitis; Cerebrospinal Fluid
PubMed: 38383424
DOI: 10.1186/s12987-024-00512-0 -
Cureus Jan 2024Varicella-zoster virus (VZV) is an alphaherpesvirus causing varicella (chickenpox) and herpes zoster. While varicella typically presents with a vesicular rash, latent...
Varicella-zoster virus (VZV) is an alphaherpesvirus causing varicella (chickenpox) and herpes zoster. While varicella typically presents with a vesicular rash, latent VZV may reactivate within the sensory ganglia causing shingles, characterized by painful vesicular rash, which may lead to neurologic complications such as aseptic meningitis. This case explores an atypical presentation in an immunocompetent young man with VZV meningitis lacking the characteristic skin rash but featuring elevated intracranial pressure. A literature review revealed rare instances of VZV-related neurologic disease without typical skin manifestations, suggesting the virus's potential to affect the central nervous system directly. Treatment with intravenous acyclovir is recommended, with ganciclovir as an alternative treatment option. This case emphasizes the importance of considering VZV meningitis in the differential diagnosis of patients presenting with viral meningitis symptoms, with or without dermatomal rash or immunocompromised conditions.
PubMed: 38370997
DOI: 10.7759/cureus.52437 -
Scientific Reports Feb 2024FilmArray® Meningitis/Encephalitis panel (FAME-p) is used to diagnose central nervous system (CNS) infections. In this study, we investigated performance of FAME-p... (Observational Study)
Observational Study
A retrospective observational study of 1000 consecutive patients tested with the FilmArray® Meningitis/Encephalitis panel: clinical diagnosis at discharge and microbiological findings.
FilmArray® Meningitis/Encephalitis panel (FAME-p) is used to diagnose central nervous system (CNS) infections. In this study, we investigated performance of FAME-p compared to comparator assays (CA), and for the first time, clinical diagnosis at discharge (CDD). 1000 consecutive patients with a cerebrospinal fluid (CSF) sample analyzed with FAME-p were identified. As CA, culture, polymerase chain reaction and cryptococcal antigen test were used. Medical records of patients were obtained. A CDD of CNS infection was made in 139 of 1000 CSF samples. FAME-p was positive in 66 samples with 44 viral and 22 bacterial agents. Thirteen FAME-p findings were not confirmed by CA, with four discrepant results remaining after comparison with the CDD. Positive percentage agreement (PPA) calculated against CA was 100%. Negative percentage agreement (NPA) calculated against CA was 94.4-99.8% for Haemophilus influenzae, Listeria monocytogenes, Streptococcus agalactiae, S. pneumoniae and varicella-zoster virus (VZV). NPA calculated against CDD was higher (compared to CA) for L. monocytogenes, S. agalactiae and VZV (100%), and lower for Escherichia coli, enterovirus and herpes simplex virus 2 (50-83.3%). NPA of FAME-p for human herpes virus 6 was difficult to interpret. Eighty-four cases received diagnosis of CNS-infection despite negative FAME-p. The four most common non-infectious etiologies were primary headache disorders, cranial nerve palsies, neuroinflammatory disorders and seizure. Although FAME-p shows good performance in diagnosis of CNS infections, result of FAME-p should be interpreted carefully. Considering infectious diseases not covered by FAME-p as well as non-infectious differential diagnoses is important in this context.
Topics: Humans; Patient Discharge; Herpesvirus 3, Human; Retrospective Studies; Central Nervous System Infections; Streptococcus pneumoniae; Meningitis; Encephalitis
PubMed: 38369552
DOI: 10.1038/s41598-024-54621-9 -
Frontiers in Immunology 2024The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the...
INTRODUCTION
The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient.
METHODS
To explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45 immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections.
RESULTS
In contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8 T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4 T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8 and CD4 T cells.
DISCUSSION
In conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Persistent Infection; Receptors, Antigen, T-Cell; Lymph Nodes; Sequence Analysis, RNA
PubMed: 38352870
DOI: 10.3389/fimmu.2024.1341985 -
BMC Medical Genomics Feb 2024We aimed to investigate the involvement of long non-coding RNA (lncRNA) in bacterial and viral meningitis in children.
BACKGROUND
We aimed to investigate the involvement of long non-coding RNA (lncRNA) in bacterial and viral meningitis in children.
METHODS
The peripheral blood of five bacterial meningitis patients, five viral meningitis samples, and five healthy individuals were collected for RNA sequencing. Then, the differentially expressed lncRNA and mRNA were detected in bacterial meningitis vs. controls, viral meningitis vs. healthy samples, and bacterial vs. viral meningitis patients. Besides, co-expression and the competing endogenous RNA (ceRNA) networks were constructed. Receiver operating characteristic curve (ROC) analysis was performed.
RESULTS
Compared with the control group, 2 lncRNAs and 32 mRNAs were identified in bacterial meningitis patients, and 115 lncRNAs and 54 mRNAs were detected in viral meningitis. Compared with bacterial meningitis, 165 lncRNAs and 765 mRNAs were identified in viral meningitis. 2 lncRNAs and 31 mRNAs were specific to bacterial meningitis, and 115 lncRNAs and 53 mRNAs were specific to viral meningitis. The function enrichment results indicated that these mRNAs were involved in innate immune response, inflammatory response, and immune system process. A total of 8 and 1401 co-expression relationships were respectively found in bacterial and viral meningitis groups. The ceRNA networks contained 1 lncRNA-mRNA pair and 4 miRNA-mRNA pairs in viral meningitis group. GPR68 and KIF5C, identified in bacterial meningitis co-expression analysis, had an area under the curve (AUC) of 1.00, while the AUC of OR52K2 and CCR5 is 0.883 and 0.698, respectively.
CONCLUSIONS
Our research is the first to profile the lncRNAs in bacterial and viral meningitis in children and may provide new insight into understanding meningitis regulatory mechanisms.
Topics: Child; Humans; RNA, Long Noncoding; Gene Regulatory Networks; MicroRNAs; RNA, Messenger; RNA, Competitive Endogenous; Sequence Analysis, RNA; Meningitis, Bacterial; Meningitis, Viral; Receptors, G-Protein-Coupled; Kinesins
PubMed: 38347610
DOI: 10.1186/s12920-024-01820-y -
Cureus Jan 2024In this case, we discuss the difficulties and challenges faced when diagnosing and treating a six-year-old boy presenting with abnormal behaviors and difficulty in...
Landau-Kleffner Syndrome, Attention-Deficit/Hyperactivity Disorder (ADHD), and Viral/Autoimmune Encephalitis: Challenges in the Diagnosis and Management of a Six-Year-Old Boy.
In this case, we discuss the difficulties and challenges faced when diagnosing and treating a six-year-old boy presenting with abnormal behaviors and difficulty in concentration and inattentiveness, followed by regression of expressive language. These symptoms were then followed by hyperactivity, bouts of anger, and difficulty sleeping. The patient was seen by a psychiatrist, and he was diagnosed with attention-deficit/hyperactivity disorder (ADHD) initially and treated with little to no improvement. He was then recommended to see a neurologist by his psychiatrist and underwent a series of investigations, which included the following: brain MRI with contrast, magnetic resonance (MR) spectroscopy, cerebrospinal fluid (CSF) routine, CSF N-methyl-D-aspartate (NMDA) receptor antibody and glutamate decarboxylase (GAD) antibody analysis, and a CSF meningitis multiplex polymerase chain reaction, thyroid function, ammonia, lactate, creatine kinase, liver function, and metabolic screening of urine organic acids (UOAs), all of which revealed no abnormalities. Vitamin D was low at 38 ng/ml (>50). An electroencephalogram (EEG) done under standard conditions and provocative stimulation was abnormal with bilateral central and frontal discharge and more activity on the right side, revealing a background activity of moderately organized alpha waves (8-13 Hz) and bursts of sharp and slow wave activities that were accentuated by photic stimulation. Polysomnography showed poor sleep efficiency of 84.7%, and rapid eye movement (REM) stage was not reached due to interrupted sleep. He was then diagnosed with epileptic encephalopathy and Landau-Kleffner syndrome (LKS). The patient was prescribed sodium valproate, intravenous immunoglobulin (IVIG), and pulse steroids, with no major improvement, risperidone was added but was poorly tolerated, and the dose tapered off and eventually discontinued. Methylphenidate was the prescribed starting at 5 mg, and the dose was gradually increased to 20 mg/day given separately as 10 mg twice a day. A week later, melatonin 2 mg was added. Three months, later the EEG was repeated and was normal, and sodium valproate was tapered off and eventually discontinued. Later on that year, he was diagnosed with COVID-19 and developed acute myositis as a complication, methylphenidate was stopped, and only sertraline and melatonin were continued. MRI was repeated only this time, showing evidence of viral/autoimmune encephalitis (AIE) sequela, and IV corticosteroids were given alongside IVIG. He was discharged on prednisolone, and a month later, major improvements were seen in all aspects.
PubMed: 38344501
DOI: 10.7759/cureus.52133 -
Journal of Virology Mar 2024Lymphocytic choriomeningitis virus (LCMV) is a bisegmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in...
UNLABELLED
Lymphocytic choriomeningitis virus (LCMV) is a bisegmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in immunocompromized populations, and as the prototypical arenavirus, acts as a model for the many serious human pathogens within this group. Here, we examined the dependence of LCMV multiplication on cellular trafficking components using a recombinant LCMV expressing enhanced green fluorescent protein in conjunction with a curated siRNA library. The screen revealed a requirement for subunits of both the coat protein 1 (COPI) coatomer and adapter protein 4 (AP-4) complexes. By rescuing a recombinant LCMV harboring a FLAG-tagged glycoprotein (GP-1) envelope spike (rLCMV-GP1-FLAG), we showed infection resulted in marked co-localization of individual COPI and AP-4 components with both LCMV nucleoprotein (NP) and GP-1, consistent with their involvement in viral processes. To further investigate the role of both COPI and AP-4 complexes during LCMV infection, we utilized the ARF-I inhibitor brefeldin A (BFA) that prevents complex formation. Within a single 12-h cycle of virus multiplication, BFA pre-treatment caused no significant change in LCMV-specific RNA synthesis, alongside no significant change in LCMV NP expression, as measured by BFA time-of-addition experiments. In contrast, BFA addition resulted in a significant drop in released virus titers, approaching 50-fold over the same 12-h period, rising to over 600-fold over 24 h. Taken together, these findings suggest COPI and AP-4 complexes are important host cell factors required for the formation and release of infectious LCMV.
IMPORTANCE
Arenaviruses are rodent-borne, segmented, negative-sense RNA viruses, with several members responsible for fatal human disease, with the prototypic member lymphocytic choriomeningitis virus (LCMV) being under-recognised as a pathogen capable of inflicting neurological infections with fatal outcome. A detailed understanding of how arenaviruses subvert host cell processes to complete their multiplication cycle is incomplete. Here, using a combination of gene ablation and pharmacological inhibition techniques, we showed that host cellular COPI and AP-4 complexes, with native roles in cellular vesicular transport, were required for efficient LCMV growth. We further showed these complexes acted on late stages of the multiplication cycle, post-gene expression, with a significant impact on infectious virus egress. Collectively, our findings improve the understanding of arenaviruses host-pathogen interactions and reveal critical cellular trafficking pathways required during infection.
Topics: Animals; Humans; Chlorocebus aethiops; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Vero Cells; Virus Replication; Adaptor Protein Complex 4; Coat Protein Complex I
PubMed: 38334330
DOI: 10.1128/jvi.02006-23 -
Cureus Jan 2024Background Delays in diagnosis and treatment of central nervous system (CNS) infections can lead to significant morbidity and mortality among children and adults. Prior...
Diagnostic Accuracy of Cerebrospinal Fluid Multiplex Polymerase Chain Reaction Panel Testing in Patients With Suspected Central Nervous System Infections: A Multi-Center Study in the United Arab Emirates.
Background Delays in diagnosis and treatment of central nervous system (CNS) infections can lead to significant morbidity and mortality among children and adults. Prior antibiotic treatment is a major hurdle to accurate diagnosis due to falsely negative cerebrospinal fluid (CSF) cultures in partially treated patients. Increasingly, molecular diagnostic methods using multiplex polymerase chain reaction (mPCR) testing on CSF samples are being utilized in clinical practice for timely and accurate diagnosis. However, there is no data regarding the diagnostic accuracy or clinical impact of CSF mPCR testing in the Middle East region. We sought to compare the diagnostic accuracy of an automated mPCR CSF panel with routine CSF culture, the current gold standard, in the United Arab Emirates (UAE). Methods This single-gated, multi-center, diagnostic accuracy study included patients from birth onwards who were admitted to any of the three participating hospitals with an initial diagnosis of meningitis or encephalitis, between January 2017 and March 2021, and had CSF samples collected for mPCR and culture. Sociodemographic, clinical, and molecular data were collected for all. Results A total of 353 CSF samples were collected from patients from 0-90 years old hospitalized for suspected CNS infection. Children constituted 51% of the study population, and males were slightly over-represented (55.2%). Pathogens were detected by mPCR in 78 (22%) CSF samples, of which 19 (24%) were bacteria and 59 (76%) were viruses. No fungal pathogens were detected. Enteroviruses were the most prevalent CNS pathogen among our cohort (40%), followed by (HSV-2) (12.5%). Children constituted 69% of positive samples for enterovirus, while HSV-2 was exclusively detected among adults. Using CSF culture as the diagnostic gold standard, the mPCR panel demonstrated high specificity (100%) and sensitivity (96.3%) in diagnosing CNS infection among all age groups. mPCR testing demonstrated a high overall percentage of agreement (OPA) with CSF culture (98.9%). Patients with bacterial meningitis had a significantly longer hospitalization (p=0.004) and duration of antibiotic therapy (p=0.001) compared to those with viral meningitis. Three CSF samples were negative on mPCR testing but positive on culture. These pathogens included: methicillin-sensitive (MSSA)and (MTB). In addition, 13 patients had negative CSF cultures but tested positive on CSF mPCR. These pathogens included (seven patients), (three patients), (two patients), and (one patient). All discordant results were confirmed by reviewing the patient's clinical presentation, CSF analysis, clinical course, and final diagnosis. Conclusion CSF mPCR panel is a highly sensitive and specific diagnostic tool for the diagnosis of CNS infections among all age groups in the UAE. Routine use of CSF mPCR panels can decrease healthcare costs by reducing the length of stay and can also aid antibiotic stewardship efforts by reducing antibiotic overuse in patients with viral CSF infections. CSF culture and mPCR complement each other by identifying CNS pathogens in patients with prior antibiotic exposure who would otherwise be missed if relying on CSF culture alone. However, concomitant CSF culture samples should be sent to avoid missing unusual CNS pathogens.
PubMed: 38333447
DOI: 10.7759/cureus.51906