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Cureus Mar 2024Drug-induced aseptic meningitis is a rare condition that occurs because of an adverse reaction to medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and...
Drug-induced aseptic meningitis is a rare condition that occurs because of an adverse reaction to medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Unlike bacterial or viral meningitis, aseptic meningitis is not caused by an infection, but rather by an inflammatory response. This condition creates a challenge since patients with aseptic meningitis often present with classic clinical meningeal symptoms, including fever, headache, and neck stiffness. We present a case of a patient with NSAID-induced aseptic meningitis and highlight the importance for healthcare providers to have a high index of suspicion for drug-induced aseptic meningitis in patients presenting with symptoms of meningitis with negative cerebrospinal fluid analysis and culture.
PubMed: 38690497
DOI: 10.7759/cureus.57349 -
Cell Reports May 2024The maintenance of antigen-specific CD8 T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8 T cell loss are not completely...
The maintenance of antigen-specific CD8 T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8 T cell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8 T cells would be of significant benefit for developing novel strategies of promoting T cell persistence. Here, we demonstrate that murine CD8 T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8 T cells. Sel1L loss limits CD8 T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8 T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.
Topics: Animals; Humans; Mice; Acute Disease; CD8-Positive T-Lymphocytes; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; Immunologic Memory; Intracellular Signaling Peptides and Proteins; Lymphocytic Choriomeningitis; Mice, Inbred C57BL; Proteins; RNA-Binding Proteins; Male; Female
PubMed: 38687642
DOI: 10.1016/j.celrep.2024.114156 -
Viruses Apr 2024Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and...
Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and apathogenic strains. Despite remarkable genetic similarity, the viscerotropic WE strain of LCMV causes a fatal LASV fever-like hepatitis in non-human primates (NHPs) while the mouse-adapted Armstrong (ARM) strain of LCMV is deeply attenuated in NHPs and can vaccinate against LCMV-WE challenge. Here, we demonstrate that internalization of WE is more sensitive to the depletion of membrane cholesterol than ARM infection while ARM infection is more reliant on endosomal acidification. LCMV-ARM induces robust NF-κB and interferon response factor (IRF) activation while LCMV-WE seems to avoid early innate sensing and failed to induce strong NF-κB and IRF responses in dual-reporter monocyte and epithelial cells. Toll-like receptor 2 (TLR-2) signaling appears to play a critical role in NF-κB activation and the silencing of TLR-2 shuts down IL-6 production in ARM but not in WE-infected cells. Pathogenic LCMV-WE infection is poorly recognized in early endosomes and failed to induce TLR-2/Mal-dependent pro-inflammatory cytokines. Following infection, Interleukin-1 receptor-associated kinase 1 (IRAK-1) expression is diminished in LCMV-ARM- but not LCMV-WE-infected cells, which indicates it is likely involved in the LCMV-ARM NF-κB activation. By confocal microscopy, ARM and WE strains have similar intracellular trafficking although LCMV-ARM infection appears to coincide with greater co-localization of early endosome marker EEA1 with TLR-2. Both strains co-localize with Rab-7, a late endosome marker, but the interaction with LCMV-WE seems to be more prolonged. These findings suggest that LCMV-ARM's intracellular trafficking pathway may facilitate interaction with innate immune sensors, which promotes the induction of effective innate and adaptive immune responses.
Topics: Lymphocytic choriomeningitis virus; Immunity, Innate; Animals; Virus Internalization; Humans; Mice; Toll-Like Receptor 2; Endosomes; NF-kappa B; Signal Transduction; Cell Line; Lymphocytic Choriomeningitis; Epithelial Cells
PubMed: 38675975
DOI: 10.3390/v16040635 -
Frontiers in Immunology 2024Blindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including...
Blindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including age-related macular degeneration, dysregulated immune response-mediated retinal degeneration has been found to play a critical role in the disease pathogenesis. To better understand the pathogenic mechanisms underlying the retinal degeneration, we used a mouse model of systemic immune activation where we infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13. Here, we evaluated the effects of LCMV infection and present a comprehensive discovery-based proteomic investigation using tandem mass tag (TMT) labeling and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Changes in protein regulation in the posterior part of the eye, neuroretina, and RPE/choroid were compared to those in the spleen as a secondary lymphoid organ and to the kidney as a non-lymphoid but encapsulated organ at 1, 8, and 28 weeks of infection. Using bioinformatic tools, we found several proteins responsible for maintaining normal tissue homeostasis to be differentially regulated in the neuroretina and the RPE/choroid during the degenerative process. Additionally, in the organs we observed, several important protein pathways contributing to cellular homeostasis and tissue development were perturbed and associated with LCMV-mediated inflammation, promoting disease progression. Our findings suggest that the response to a systemic chronic infection differs between the neuroretina and the RPE/choroid, and the processes induced by chronic systemic infection in the RPE/choroid are not unlike those induced in non-immune-privileged organs such as the kidney and spleen. Overall, our data provide detailed insight into several molecular mechanisms of neuroretinal degeneration and highlight various novel protein pathways that further suggest that the posterior part of the eye is not an isolated immunological entity despite the existence of neuroretinal immune privilege.
Topics: Animals; Mice; Proteomics; Disease Models, Animal; Retinal Degeneration; Lymphocytic choriomeningitis virus; Mice, Inbred C57BL; Lymphocytic Choriomeningitis; Tandem Mass Spectrometry; Proteome; Retina; Chromatography, Liquid; Choroid
PubMed: 38665911
DOI: 10.3389/fimmu.2024.1374617 -
Nature Communications Apr 2024Human parechoviruses (PeV-A) are increasingly being recognized as a cause of infection in neonates and young infants, leading to a spectrum of clinical manifestations...
Human parechoviruses (PeV-A) are increasingly being recognized as a cause of infection in neonates and young infants, leading to a spectrum of clinical manifestations ranging from mild gastrointestinal and respiratory illnesses to severe sepsis and meningitis. However, the host factors required for parechovirus entry and infection remain poorly characterized. Here, using genome-wide CRISPR/Cas9 loss-of-function screens, we identify myeloid-associated differentiation marker (MYADM) as a host factor essential for the entry of several human parechovirus genotypes including PeV-A1, PeV-A2 and PeV-A3. Genetic knockout of MYADM confers resistance to PeV-A infection in cell lines and in human gastrointestinal epithelial organoids. Using immunoprecipitation, we show that MYADM binds to PeV-A1 particles via its fourth extracellular loop, and we identify critical amino acid residues within the loop that mediate binding and infection. The demonstrated interaction between MYADM and PeV-A1, and its importance specifically for viral entry, suggest that MYADM is a virus receptor. Knockout of MYADM does not reduce PeV-A1 attachment to cells pointing to a role at the post-attachment stage. Our study suggests that MYADM is a multi-genotype receptor for human parechoviruses with potential as an antiviral target to combat disease associated with emerging parechoviruses.
Topics: Humans; Cell Line; CRISPR-Cas Systems; HEK293 Cells; Organoids; Parechovirus; Picornaviridae Infections; Protein Binding; Receptors, Virus; Virus Internalization
PubMed: 38658526
DOI: 10.1038/s41467-024-47825-0 -
Cureus Mar 2024Cerebral palsy (CP) is a neurodevelopmental disorder that affects motor function and is often accompanied by secondary musculoskeletal issues. Severe scoliosis, a...
Cerebral palsy (CP) is a neurodevelopmental disorder that affects motor function and is often accompanied by secondary musculoskeletal issues. Severe scoliosis, a lateral curvature of the spine over 40 degrees, poses a significant challenge for individuals with CP, impacting their mobility and overall well-being. While the association between scoliosis and gastrointestinal complications is acknowledged, the occurrence of colonic volvulus with necrosis in the context of CP and severe scoliosis is rare and complex. This case report emphasizes the importance of clinical awareness in managing gastrointestinal complications in patients with CP and severe scoliosis. An 11-year-old female presented with gastroenteritis and a concurrent viral upper respiratory tract infection. She experienced complications such as greenish vomiting, hematemesis, abdominal distention, and constipation. The patient has a medical history of epilepsy and was diagnosed with quadriplegic CP at four months old due to viral meningitis. She is currently on anti-epileptic medications and receives regular follow-ups with neurology. Severe lumbar scoliosis of more than 50 degrees Cobb angle is also noted. Physical examination revealed dehydration, bilious content in nasogastric tube (NGT) aspiration, tender abdomen, and an empty digital rectal examination. Some laboratory findings showed elevated levels of erythrocyte sedimentation rate (ESR), prothrombin time (PT), blood urea nitrogen (BUN), and sodium, while albumin levels were decreased, and white blood cell (WBC) count was mildly elevated. Abdominal computed tomography (CT) with contrast showed a distended ascending colon with air and swirling of the mesentery. The distal half of the large bowel was not dilated, and fecal matter was present. The small bowel appeared to be collapsed, and there was moderate free fluid in the peritoneal cavity, indicating colonic volvulus involving the proximal large bowel. The patient underwent surgery, which involved deflating and removing the distended colon, resecting the gangrenous colon, and performing an ilio-sigmoid anastomosis to restore gastrointestinal continuity. Postoperatively, the patient received close monitoring in the pediatric intensive care unit (PICU), received total parenteral nutrition (TPN) for five days, gradually progressed feeding, and showed overall improvement in her condition. In conclusion, this case report highlights a rare occurrence of colonic volvulus in a patient with CP and severe scoliosis. It emphasizes the complex relationship between neurological and musculoskeletal disorders in gastrointestinal complications. A multidisciplinary approach is important for optimal management. It shows the importance of musculoskeletal factors in patients with neurological conditions. Overall, it contributes to the medical literature and emphasizes tailored management strategies for gastrointestinal issues in such patients.
PubMed: 38650790
DOI: 10.7759/cureus.56743 -
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 -
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