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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 -
American Family Physician Apr 2021Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include... (Review)
Review
Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include suspected central nervous system infection or subarachnoid hemorrhage. CSF analysis is not necessarily diagnostic but can be useful in the evaluation of other neurologic conditions, such as spontaneous intracranial hypotension, idiopathic intracranial hypertension, multiple sclerosis, Guillain-Barré syndrome, and malignancy. Bacterial meningitis has a high mortality rate and characteristic effects on CSF white blood cell counts, CSF protein levels, and the CSF:serum glucose ratio. CSF culture can identify causative organisms and antibiotic sensitivities. Viral meningitis can present similarly to bacterial meningitis but usually has a low mortality rate. Adjunctive tests such as CSF lactate measurement, latex agglutination, and polymerase chain reaction testing can help differentiate between bacterial and viral causes of meningitis. Immunocompromised patients may have meningitis caused by tuberculosis, neurosyphilis, or fungal or parasitic infections. Subarachnoid hemorrhage has a high mortality rate, and rapid diagnosis is key to improve outcomes. Computed tomography of the head is nearly 100% sensitive for subarachnoid hemorrhage in the first six hours after symptom onset, but CSF analysis may be required if there is a delay in presentation or if imaging findings are equivocal. Xanthochromia and an elevated red blood cell count are characteristic CSF findings in patients with subarachnoid hemorrhage. Leptomeningeal carcinomatosis can mimic central nervous system infection. It has a poor prognosis, and large-volume CSF cytology is diagnostic.
Topics: Central Nervous System Bacterial Infections; Central Nervous System Fungal Infections; Central Nervous System Infections; Central Nervous System Parasitic Infections; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Culture Techniques; Eosinophils; Glucose; Humans; Leukocytes; Lymphocytes; Meningeal Carcinomatosis; Meningitis, Cryptococcal; Neurosyphilis; Neutrophils; Polymerase Chain Reaction; Reference Values; Spinal Puncture; Subarachnoid Hemorrhage; Tuberculosis, Central Nervous System
PubMed: 33788511
DOI: No ID Found -
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 -
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 -
Nature Oct 2022Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection. Here we examine the underlying basis for...
Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1TCF1 stem-like CD8 T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8 T cells that resemble highly functional effector CD8 T cells seen after an acute viral infection. The generation of these qualitatively superior CD8 T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1TCF1 stem-like CD8 T cells, also referred to as precursors of exhausted CD8 T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8 T cells emerging from the stem-like CD8 T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
Topics: CD8-Positive T-Lymphocytes; Cell Differentiation; Drug Therapy, Combination; Humans; Interleukin Receptor Common gamma Subunit; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Interleukin-2 Receptor beta Subunit; Lymphocytic Choriomeningitis; Programmed Cell Death 1 Receptor; T Cell Transcription Factor 1
PubMed: 36171288
DOI: 10.1038/s41586-022-05257-0 -
Infection and Drug Resistance 2020Acute community-acquired bacterial meningitis (ABM) in children continues to have high rates of neurological morbidity and mortality despite the overall declining rates... (Review)
Review
Acute community-acquired bacterial meningitis (ABM) in children continues to have high rates of neurological morbidity and mortality despite the overall declining rates of infection attributed to the use of vaccines and intrapartum Group B prophylaxis. Prompt diagnosis and early antibiotic therapy are crucial and should not be delayed to obtain cranial imaging. Differentiating bacterial from viral meningitis continues to be a clinical dilemma especially in patients with previous antibiotic exposure. Clinical models and inflammatory biomarkers can aid clinicians in their diagnostic approach. Multiplex polymerase chain reaction and metagenomic next-generation sequencing are promising tools that can help in early and accurate diagnosis. This review will present the epidemiology of ABM in children, indications of cranial imaging, role of different models and serum biomarkers in diagnosing ABM, and management including the use of adjunctive therapies and methods of prevention.
PubMed: 33204125
DOI: 10.2147/IDR.S240162 -
Immunity Dec 2019T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have...
T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1 Tcf-1 CD8 T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1 CD8 T cells initially differentiated into a transitory population of CD101Tim3 cells that later converted into CD101 Tim3 cells. Recently generated CD101Tim3 cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101Tim3 CD8 T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.
Topics: Animals; Antigens, CD; Biomarkers; CD8-Positive T-Lymphocytes; CX3C Chemokine Receptor 1; Female; Granzymes; Hepatitis A Virus Cellular Receptor 2; Hepatocyte Nuclear Factor 1-alpha; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Male; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor
PubMed: 31810882
DOI: 10.1016/j.immuni.2019.11.002 -
Cell Mar 2021How early events in effector T cell (T) subsets tune memory T cell (T) responses remains incompletely understood. Here, we systematically investigated metabolic...
How early events in effector T cell (T) subsets tune memory T cell (T) responses remains incompletely understood. Here, we systematically investigated metabolic factors in fate determination of T and T cells using in vivo pooled CRISPR screening, focusing on negative regulators of T responses. We found that amino acid transporters Slc7a1 and Slc38a2 dampened the magnitude of T differentiation, in part through modulating mTORC1 signaling. By integrating genetic and systems approaches, we identified cellular and metabolic heterogeneity among T cells, with terminal effector differentiation associated with establishment of metabolic quiescence and exit from the cell cycle. Importantly, Pofut1 (protein-O-fucosyltransferase-1) linked GDP-fucose availability to downstream Notch-Rbpj signaling, and perturbation of this nutrient signaling axis blocked terminal effector differentiation but drove context-dependent T proliferation and T development. Our study establishes that nutrient uptake and signaling are key determinants of T cell fate and shape the quantity and quality of T responses.
Topics: Amino Acid Transport Systems; Amino Acids; Animals; CD8-Positive T-Lymphocytes; CRISPR-Cas Systems; Cell Cycle; Cell Differentiation; Disease Models, Animal; Female; Gene Knock-In Techniques; Immunologic Memory; Lymphocytic Choriomeningitis; Male; Mice; Mice, Transgenic; Precursor Cells, T-Lymphoid; Signal Transduction
PubMed: 33636132
DOI: 10.1016/j.cell.2021.02.021 -
MBio Aug 2021Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional...
Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional diagnostic workflows largely rely on pathogen-specific tests, sometimes over days to weeks, whereas metagenomic next-generation sequencing (mNGS) profiles all nucleic acid in a sample. In this single-center, prospective study, 68 hospitalized patients with known ( = 44) or suspected ( = 24) CNS infections underwent mNGS from RNA and DNA to identify potential pathogens and also targeted sequencing of viruses using hybrid capture. Using a computational metagenomic classification pipeline based on KrakenUniq and BLAST, we detected pathogen nucleic acid in cerebrospinal fluid (CSF) from 22 subjects, 3 of whom had no clinical diagnosis by routine workup. Among subjects diagnosed with infection by serology and/or peripheral samples, we demonstrated the utility of mNGS to detect pathogen nucleic acid in CSF, importantly for the Ixodes scapularis tick-borne pathogens Powassan virus, Borrelia burgdorferi, and Anaplasma phagocytophilum. We also evaluated two methods to enhance the detection of viral nucleic acid, hybrid capture and methylated DNA depletion. Hybrid capture nearly universally increased viral read recovery. Although results for methylated DNA depletion were mixed, it allowed the detection of varicella-zoster virus DNA in two samples that were negative by standard mNGS. Overall, mNGS is a promising approach that can test for multiple pathogens simultaneously, with efficacy similar to that of pathogen-specific tests, and can uncover geographically relevant infectious CNS disease, such as tick-borne infections in New England. With further laboratory and computational enhancements, mNGS may become a mainstay of workup for encephalitis and meningitis. Meningitis and encephalitis are leading global causes of central nervous system (CNS) disability and mortality. Current diagnostic workflows remain inefficient, requiring costly pathogen-specific assays and sometimes invasive surgical procedures. Despite intensive diagnostic efforts, 40 to 60% of people with meningitis or encephalitis have no clear cause of CNS disease identified. As diagnostic uncertainty often leads to costly inappropriate therapies, the need for novel pathogen detection methods is paramount. Metagenomic next-generation sequencing (mNGS) offers the unique opportunity to circumvent these challenges using unbiased laboratory and computational methods. Here, we performed comprehensive mNGS from 68 prospectively enrolled patients with known ( = 44) or suspected ( = 24) CNS viral infection from a single center in New England and evaluated enhanced methods to improve the detection of CNS pathogens, including those not traditionally identified in the CNS by nucleic acid detection. Overall, our work helps elucidate how mNGS can become integrated into the diagnostic toolkit for CNS infections.
Topics: Adult; Aged; Central Nervous System Viral Diseases; Encephalitis; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Meningitis; Metagenome; Metagenomics; Middle Aged; Prospective Studies; Viruses
PubMed: 34465023
DOI: 10.1128/mBio.01143-21