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Frontiers in Immunology 2024Macrophage function is determined by microenvironment and origin. Brain and retinal microglia are both derived from yolk sac progenitors, yet their microenvironments...
INTRODUCTION
Macrophage function is determined by microenvironment and origin. Brain and retinal microglia are both derived from yolk sac progenitors, yet their microenvironments differ. Utilizing single-cell RNA sequencing (scRNA-seq) data from mice, we tested the hypothesis that retinal and brain microglia exhibit distinct transcriptional profiles due to their unique microenvironments.
METHODS
Eyes and brains from 2-4 month wildtype mice were combined (20 eyes; 3 brains) to yield one biologically diverse sample per organ. Each tissue was digested into single cell suspensions, enriched for immune cells, and sorted for scRNA-seq. Analysis was performed in Seurat v3 including clustering, integration, and differential expression. Multi-parameter flow cytometry was used for validation of scRNA-seq results. Lymphocytic choriomeningitis virus (LCMV) Clone 13, which produces a systemic, chronic, and neurotropic infection, was used to validate scRNA-seq and flow cytometry results .
RESULTS
Cluster analysis of integrated gene expression data from eye and brain identified 6 microglial clusters. Differential expression analysis revealed that eye microglia were enriched for more pro-inflammatory processes including antigen processing via MHC class I (14.0-fold, and ) and positive regulation of T-cell immunity (8.4-fold) compared to brain microglia. Multi-parameter flow cytometry confirmed that retinal microglia expressed 3.2-fold greater H2-Db and 263.3-fold more H2-Kb than brain microglia. On Day 13 and 29 after LCMV infection, CD8 T-cell density was greater in the retina than the brain.
DISCUSSION
Our data demonstrate that the microenvironment of retina and brain differs, resulting in microglia-specific gene expression changes. Specifically, retinal microglia express greater MHC class I by scRNA-seq and multi-parameter flow cytometry, resulting in a possibly enhanced capability to stimulate CD8 T-cell inflammation during LCMV infection. These results may explain tissue-specific differences between retina and brain during systemic viral infections and CD8 T-cell driven autoimmune disease.
Topics: Animals; Microglia; Mice; Retina; Brain; Mice, Inbred C57BL; Lymphocytic choriomeningitis virus; Histocompatibility Antigens Class I; T-Lymphocytes; Inflammation; Lymphocytic Choriomeningitis; Single-Cell Analysis; CD8-Positive T-Lymphocytes; Transcriptome
PubMed: 38799448
DOI: 10.3389/fimmu.2024.1399989 -
Viruses May 2024Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration...
Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections.
Topics: Animals; Mice; Lymphocytic choriomeningitis virus; Immunotherapy; Lymphocytic Choriomeningitis; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Fibrosis; Mice, Inbred C57BL; Immune Checkpoint Inhibitors; Viral Load; Spleen; Disease Models, Animal; Chronic Disease; Female
PubMed: 38793680
DOI: 10.3390/v16050799 -
Viruses Apr 2024West Nile virus (WNV) is an arbovirus spread primarily by mosquitoes, with humans being a dead-end host. WNV was introduced to Florida in 2001, with 467 confirmed cases...
West Nile virus (WNV) is an arbovirus spread primarily by mosquitoes, with humans being a dead-end host. WNV was introduced to Florida in 2001, with 467 confirmed cases since. It is estimated that 80 percent of cases are asymptomatic, with mild cases presenting as a non-specific flu-like illness. Currently, detection of WNV in humans occurs primarily in healthcare settings via RT-PCR or CSF IgM when patients present with severe manifestations of disease including fever, meningitis, encephalitis, or acute flaccid paralysis. Given the short window of detectable viremia and requirement for CSF sampling, most WNV infections never receive an official diagnosis. This study utilized enzyme-linked immunosorbent assay (ELISA) to detect WNV IgG antibodies in 250 patient serum and plasma samples collected at Tampa General Hospital during 2020 and 2021. Plaque reduction neutralization tests were used to confirm ELISA results. Out of the 250 patients included in this study, 18.8% of them were IgG positive, consistent with previous WNV exposure. There was no relationship between WNV exposure and age or sex.
Topics: Humans; West Nile virus; West Nile Fever; Florida; Male; Female; Antibodies, Viral; Middle Aged; Seroepidemiologic Studies; Immunoglobulin G; Adult; Aged; Young Adult; Adolescent; Aged, 80 and over; Enzyme-Linked Immunosorbent Assay; Hospitalization; Immunoglobulin M
PubMed: 38793601
DOI: 10.3390/v16050719 -
Pathogens (Basel, Switzerland) May 2024West Nile virus (WNV) neuroinvasive disease (WNND) occurs in approximately 1 percent of WNV-infected patients and typically presents as encephalitis, meningitis, or...
West Nile virus (WNV) neuroinvasive disease (WNND) occurs in approximately 1 percent of WNV-infected patients and typically presents as encephalitis, meningitis, or acute flaccid paralysis (AFP). WNND remains a difficult inpatient diagnosis, creating significant challenges for prognostication and therapy selection. We characterized the clinical and diagnostic features of WNND cases at two major academic medical centers in New York City in routine clinical practice. We retrospectively reviewed the charts of thirty-six patients with WNND, including twenty-six encephalitis, four meningitis, and six AFP cases. The most common presenting symptoms were fever (86.1%) and gastrointestinal symptoms (38.9%) in addition to altered mental status (72.2%), lethargy (63.9%), gait disturbances (46.2%), and headache (44.4%). Fourteen (48.3%) patients displayed acute magnetic resonance imaging (MRI) findings, particularly T2 hyperintensities in the bilateral thalami, brainstem, and deep white matter. New York State Department of Health WNV CSF IgM testing was utilized for diagnosis in 58.3% of patients; however, just 38.1% had the result by discharge, compared to 85.6% of those who underwent serum IgM testing. The median length of stay was 13.5 days, 38.9% were intubated, and three patients (8.9%) died during acute hospitalization. Our findings underscore the morbidity, mortality, and diagnostic challenges of WNND, suggesting the potential utility of serum IgM testing in combination with confirmatory CSF testing to expedite diagnosis in the acute setting.
PubMed: 38787234
DOI: 10.3390/pathogens13050382 -
Journal of Neuroimmunology May 2024The extracellular matrix protein tenascin-C has been discovered to be an important regulator of the response to tissue injury and repair in cerebrovascular diseases....
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.
PubMed: 38776710
DOI: 10.1016/j.jneuroim.2024.578373 -
Microbiology Spectrum May 2024Enterovirus A71 (EV-A71) is associated with neurological conditions such as acute meningitis and encephalitis. The virus is detected in the bloodstream, and high blood...
Enterovirus A71 (EV-A71) is associated with neurological conditions such as acute meningitis and encephalitis. The virus is detected in the bloodstream, and high blood viral loads are associated with central nervous system (CNS) manifestations. We used an blood-brain barrier (BBB) model made up of human brain-like endothelial cells (hBLECs) and brain pericytes grown in transwell systems to investigate whether three genetically distinct EV-A71 strains (subgenogroups C1, C1-like, and C4) can cross the human BBB. EV-A71 poorly replicated in hBLECs, which released moderate amounts of infectious viruses from their luminal side and trace amounts of infectious viruses from their basolateral side. The barrier properties of hBLECs were not impaired by EV-A71 infection. We investigated the passage through hBLECs of EV-A71-infected white blood cells. EV-A71 strains efficiently replicated in immune cells, including monocytes, neutrophils, and NK/T cells. Attachment to hBLECs of immune cells infected with the C1-like virus was higher than attachment of cells infected with C1-06. EV-A71 infection did not impair the transmigration of immune cells through hBLECs. Overall, EV-A71 targets different white blood cell populations that have the potential to be used as a Trojan horse to cross hBLECs more efficiently than cell-free EV-A71 particles.IMPORTANCEEnterovirus A71 (EV-A71) was first reported in the USA, and numerous outbreaks have since occurred in Asia and Europe. EV-A71 re-emerged as a new multirecombinant strain in 2015 in Europe and is now widespread. The virus causes hand-foot-and-mouth disease in young children and is involved in nervous system infections. How the virus spreads to the nervous system is unclear. We investigated whether white blood cells could be infected by EV-A71 and transmit it across human endothelial cells mimicking the blood-brain barrier protecting the brain from adverse effects. We found that endothelial cells provide a strong roadblock to prevent the passage of free virus particles but allow the migration of infected immune cells, including monocytes, neutrophils, and NK/T cells. Our data are consistent with the potential role of immune cells in the pathogenesis of EV-A71 infections by spreading the virus in the blood and across the human blood-brain barrier.
PubMed: 38752731
DOI: 10.1128/spectrum.00690-24 -
Current Research in Microbial Sciences 2024Oropouche virus (OROV) is a member of the family and the causative agent of a dengue-like febrile illness transmitted by mosquitoes. Although mild symptoms generally...
Oropouche virus (OROV) is a member of the family and the causative agent of a dengue-like febrile illness transmitted by mosquitoes. Although mild symptoms generally occur, complications such as encephalitis and meningitis may develop. A lack of proper diagnosis, makes it a potential candidate for new epidemics and outbreaks like other known arboviruses such as Dengue, Yellow Fever and Zika virus. The study of natural molecules as potential antiviral compounds is a promising alternative for antiviral therapies. Wedelolactone (WDL) has been demonstrated to inhibit some viral proteins and virus replication, making it useful to target a wide range of viruses. In this study, we report the effects of WDL on the OROV N-terminal polymerase and its potential inhibitory effects on several steps of viral infection in mammalian cells , which revealed that WDL indeed acts as a potential inhibitor molecule against OROV infection.
PubMed: 38745914
DOI: 10.1016/j.crmicr.2024.100238 -
Heliyon May 2024Acute meningitis is a disease with case fatality and disability rate that is dependent on the causative agent.
BACKGROUND
Acute meningitis is a disease with case fatality and disability rate that is dependent on the causative agent.
OBJECTIVE
Determine the meningitis trend in Iraq from 2007 to 2023 using a joinpoint regression at national and sub-national levels and describe the epidemiology.
METHODS
Joinpoint regression model was used on surveillance data from Jan 2007 until May 2023, to calculate annual and average annual percent changes to determine the trend. Meningitis total count was modelled by year of reporting and province using the log transformation and Poisson variance. Best-fit model was chosen based on the weighted BIC criteria as the final point.
RESULTS
Bacterial meningitis was higher than viral meningitis from 2007 to 2018, then viral meningitis started to exceed till 2023. Meningococcal meningitis was lower than other bacterial and viral meningitis from 2007 to 2023. Most meningitis cases across the years were lower than 15 years, at almost 80 %, while 20 %-40 % were lower than one year. Across all years, 55 % of the cases were males; apart from 2019, 70 % were females.
CONCLUSION
In Iraq, viral meningitis has been the predominant type since 2018. Most meningitis patients were lower than 15-year-old males. The meningitis trend in Iraq was stable from 2007 till 2023.
PubMed: 38707473
DOI: 10.1016/j.heliyon.2024.e30088 -
Heliyon Apr 2024Central nervous system (CNS) tuberculosis is a post-primary form of tuberculosis. It has high mortality and morbidity rates despite early diagnosis and treatment. CNS... (Review)
Review
Central nervous system (CNS) tuberculosis is a post-primary form of tuberculosis. It has high mortality and morbidity rates despite early diagnosis and treatment. CNS tuberculosis can manifest as subacute/chronic meningitis, parenchymal tuberculous lesions, and spinal tuberculosis. Hematogenous spread of tuberculous bacilli to the brain results in the development of so called "rich foci" on the pial surface, ependyma, and grey-white matter junction. Rupture of these "rich foci" into the subarachnoid space triggers an intense granulomatous inflammatory reaction. Tuberculous meningitis can manifest as leptomeningitis or pachymeningitis. Intracranial parenchymal tuberculous lesions may present as tuberculoma, tuberculous abscess, cerebritis, rhombencephalitis, and encephalopathy, with atypical presentations not uncommon. Complications of CNS tuberculosis encompass hydrocephalus, syrinx formation, vasculitis, infarcts, neuritis, and enduring neurological deficits. Post-contrast 3D fluid-attenuated inversion recovery (FLAIR) and post-contrast T1 spin-echo sequences excel in detecting tuberculous meningitis compared to other conventional magnetic resonance imaging (MRI) sequences. In proton magnetic resonance spectroscopy (PMRS), the presence of a lipid peak at 1.3 ppm is indicative of tuberculous lesions. Magnetization transfer (MT) imaging enhances the detection of tuberculous lesions, as the magnetization transfer ratio (MTR) of tuberculous pathologies, owing to their high lipid content, is lower than that in bacterial or fungal pathologies and higher than that in viral pathologies. This review article delves into the various typical and atypical imaging presentations of CNS tuberculosis in MRI, along with recent advances in imaging techniques.
PubMed: 38699716
DOI: 10.1016/j.heliyon.2024.e29779 -
Virology Journal May 2024Human parechovirus, a member of the Picornaviridae family (PeVs), can lead to severe infections, including severe meningitis, meningoencephalitis, and sepsis-like...
Human parechovirus, a member of the Picornaviridae family (PeVs), can lead to severe infections, including severe meningitis, meningoencephalitis, and sepsis-like syndrome. We report a case of human parechovirus-related encephalitis in a 52-year-old woman diagnosed with glioblastoma multiforme. She underwent surgical resection in June 2022. Unfortunately, her disease recurred, and she underwent a second resection in August 2022, followed by radiation therapy and Temozolomide therapy. She presented to the hospital with acute confusion followed by seizures, necessitating intubation for airway support. A cerebrospinal fluid (CSF) sample was obtained and processed using the Biofire FilmArray, which reported the detection of HSV-1. Despite being on Acyclovir, the patient did not show signs of improvement. Consequently, a second CSF sample was obtained and sent for next-generation sequencing (NGS), which returned a positive result for Parechovirus. In this presented case, the patient exhibited symptoms of an unknown infectious cause. The utilization of NGS and metagenomic analysis helped identify Parechovirus as the primary pathogen present, in addition to previously identified HSV. This comprehensive approach facilitated a thorough assessment of the underlying infection and guided targeted treatment. In conclusion, the application of NGS techniques and metagenomic analysis proved instrumental in identifying the root cause of the infection.
Topics: Humans; Female; Middle Aged; Immunocompromised Host; Picornaviridae Infections; Parechovirus; Saudi Arabia; High-Throughput Nucleotide Sequencing; Glioblastoma; Metagenomics; Encephalitis, Viral; Herpesvirus 1, Human; Hospitalization
PubMed: 38698421
DOI: 10.1186/s12985-024-02372-4