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Inflammasome activation underlies central nervous system deterioration in HIV-associated tuberculosis

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Title: Inflammasome activation underlies central nervous system deterioration in HIV-associated tuberculosis
Authors: Marais, S
Lai, RP-J
Wilkinson, KA
Meintjes, G
O'Garra, A
Wilkinson, RJ
Item Type: Journal Article
Abstract: Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis–immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM-IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS.
Issue Date: 8-Dec-2016
Date of Acceptance: 14-Oct-2016
URI: http://hdl.handle.net/10044/1/41631
DOI: https://dx.doi.org/10.1093/infdis/jiw561
ISSN: 1537-6613
Publisher: Oxford University Press (OUP)
Start Page: 677
End Page: 686
Journal / Book Title: Journal of Infectious Diseases
Volume: 215
Issue: 5
Copyright Statement: © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 104803/Z/14/ZR
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
Infectious Diseases
Microbiology
Tuberculosis meningitis
HIV
microarray
inflammasomes
neutrophils
NLRP3 INFLAMMASOME
CEREBROSPINAL-FLUID
RECONSTITUTION
MENINGITIS
METALLOPROTEINASES
IMMUNOPATHOLOGY
SIGNATURE
FREQUENCY
DIAGNOSIS
BIOMARKER
Adult
Antiretroviral Therapy, Highly Active
Caspase 1
Caspase 3
Caspases, Initiator
Central Nervous System
Complement System Proteins
Female
HIV Infections
Humans
Immune Reconstitution Inflammatory Syndrome
Inflammasomes
Lymphocyte Count
Male
Middle Aged
Neutrophils
Prognosis
Prospective Studies
Transcriptome
Tuberculosis, Meningeal
11 Medical And Health Sciences
06 Biological Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine



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