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Archives of Virology Feb 2021Meningitis is a serious condition that affects the central nervous system. It is an inflammation of the meninges, which is the membrane that surrounds both the brain and... (Review)
Review
Meningitis is a serious condition that affects the central nervous system. It is an inflammation of the meninges, which is the membrane that surrounds both the brain and the spinal cord. Meningitis can be caused by bacterial, viral, or fungal infections. Many viruses, such as enteroviruses, herpesviruses, and influenza viruses, can cause this neurological disorder. However, enteroviruses have been found to be the underlying cause of most viral meningitis cases worldwide. With few exceptions, the clinical manifestations and symptoms associated with viral meningitis are similar for the different causative agents, which makes it difficult to diagnose the disease at early stages. The pathogenesis of viral meningitis is not clearly defined, and more studies are needed to improve the health care of patients in terms of early diagnosis and management. This review article discusses the most common causative agents, epidemiology, clinical features, diagnosis, and pathogenesis of viral meningitis.
Topics: Animals; Humans; Meningitis, Viral; Viruses
PubMed: 33392820
DOI: 10.1007/s00705-020-04891-1 -
Current Opinion in Infectious Diseases Jun 2020Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in... (Review)
Review
PURPOSE OF REVIEW
Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults.
RECENT FINDINGS
Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials.
SUMMARY
Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.
Topics: Adult; Antitubercular Agents; Child; Diagnostic Tests, Routine; Humans; Lipopolysaccharides; Mycobacterium tuberculosis; Tuberculosis, Meningeal
PubMed: 32324614
DOI: 10.1097/QCO.0000000000000648 -
Nature Mar 2023The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. Bacterial meningitis causes life-threatening infections of the...
The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8 nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.
Topics: Humans; Brain; Calcitonin Gene-Related Peptide; Meninges; Neuroimmunomodulation; Pain; NAV1.8 Voltage-Gated Sodium Channel; Meningitis, Bacterial; Streptococcus agalactiae; Streptococcus pneumoniae; Nociceptors; Receptor Activity-Modifying Protein 1; Macrophages
PubMed: 36859544
DOI: 10.1038/s41586-023-05753-x -
Immunity Nov 2022The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of...
The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II MM were abundant neonatally, whereas MHC-II MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation.
Topics: Animals; Mice; Lipopolysaccharides; Mice, Inbred C57BL; SARS-CoV-2; COVID-19; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Macrophages; Meninges
PubMed: 36323311
DOI: 10.1016/j.immuni.2022.10.005 -
Science (New York, N.Y.) Jul 2021The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here,...
The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for a reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches that harness meningeal immune cells.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Brain; Cell Movement; Central Nervous System; Central Nervous System Diseases; Dura Mater; Encephalomyelitis, Autoimmune, Experimental; Homeostasis; Meninges; Mice; Monocytes; Myeloid Cells; Neutrophils; Skull; Spinal Cord; Spinal Cord Injuries; Spine
PubMed: 34083447
DOI: 10.1126/science.abf7844 -
Cell Feb 2021Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However,...
Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.
Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Cellular Senescence; Chemokine CXCL12; Cranial Sinuses; Dura Mater; Female; Homeostasis; Humans; Immunity; Male; Mice, Inbred C57BL; Phenotype; Stromal Cells; T-Lymphocytes; Mice
PubMed: 33508229
DOI: 10.1016/j.cell.2020.12.040 -
Veterinary Journal (London, England :... 2023Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle,... (Review)
Review
Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle, SRMA is divided into two clinical courses: during the typical acute form, dogs are presented with fever, cervical hyperaesthesia, and reluctance to move. The more protracted form most probably emerges after insufficient immunosuppressive treatment or relapses, with additional neurologic deficits localized in the cervical and thoracolumbar spinal cord or multifocally. The trigger leading to SRMA still remains an unsolved riddle for immunologists and clinical neurologists. In the past, many attempts have been made to clarify the etiology of this disease without success. The purpose of writing this narrative review about SRMA is to summarize new insights on the pathogenesis of SRMA with a focus on immunologic dysregulation. Furthermore, unusual manifestations of the disease, new diagnostic approaches using possible laboratory biomarkers or diagnostic imaging tools, and potential innovative treatment strategies are discussed.
Topics: Animals; Dogs; Meningitis; Arteritis; Biomarkers; Steroids; Dog Diseases
PubMed: 37704169
DOI: 10.1016/j.tvjl.2023.106030 -
Biomarkers in Medicine Apr 2020Infectious meningitis can be caused by viral, bacterial or fungal pathogens. Despite widely available treatments, many types of infectious meningitis are still... (Review)
Review
Infectious meningitis can be caused by viral, bacterial or fungal pathogens. Despite widely available treatments, many types of infectious meningitis are still associated with significant morbidity and mortality. Delay in diagnosis contributes to poor outcomes. Cerebrospinal fluid cultures have been used traditionally but are time intensive and sensitivity is decreased by empiric treatment prior to culture. More rapid techniques such as the cryptococcal lateral flow assay (IMMY), GeneXpert MTB/Rif Ultra (Cepheid) and FilmArray multiplex-PCR (Biofire) are three examples that have drastically changed meningitis diagnostics. This review will discuss a holistic approach to diagnosing bacterial, mycobacterial, viral and fungal meningitis.
Topics: Adult; Diagnostic Techniques and Procedures; Humans; Meningitis; Time Factors
PubMed: 32270693
DOI: 10.2217/bmm-2019-0333 -
Nature May 2021Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies...
Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal, Humanized; Brain; Disease Models, Animal; Hippocampus; Humans; Immunotherapy; Inflammation; Lymphatic Vessels; Male; Meninges; Mice; Microglia; Transcription, Genetic; Vascular Endothelial Growth Factor C
PubMed: 33911285
DOI: 10.1038/s41586-021-03489-0 -
Science (New York, N.Y.) Jul 2021The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic...
The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS.
Topics: Aging; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow Cells; Cell Movement; Central Nervous System; Dura Mater; Fibroblasts; Homeostasis; Immune Privilege; Lymphopoiesis; Meninges; Mice; Plasma Cells; Single-Cell Analysis; Skull
PubMed: 34083450
DOI: 10.1126/science.abf9277