title: Inflammasome Activation Underlying Central Nervous System Deterioration in HIV-Associated Tuberculosis.
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.
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Suzaan
authors.initials: S
authors.lastname: Marais
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Rachel P J
authors.initials: RPJ
authors.lastname: Lai
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.|Tuberculosis Laboratory, The Francis Crick Institute, 1 Midland Road, London, UK.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Laboratory of Immuno regulation and Infection, The Francis Crick Institute, London, UK.|National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.|Tuberculosis Laboratory, The Francis Crick Institute, 1 Midland Road, London, UK.|Department of Medicine, Imperial College London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D020170:Caspase 1 / Q000097:blood / Q000134:cerebrospinal fluid; D053148:Caspase 3 / Q000097:blood / Q000134:cerebrospinal fluid; D053471:Caspases, Initiator / Q000097:blood / Q000134:cerebrospinal fluid; D002490:Central Nervous System / Q000821:virology*; D003165:Complement System Proteins / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology*; D058847:Inflammasomes / Q000097:blood*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D059467:Transcriptome; D014390:Tuberculosis, Meningeal / Q000276:immunology* / Q000821:virology
chemical_list: D058847:Inflammasomes; D003165:Complement System Proteins; C505407:CASP3 protein, human; C093516:CASP4 protein, human; D053148:Caspase 3; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: HIV; Tuberculosis meningitis; inflammasomes; microarray; neutrophils