Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 215, Issue 5, Pages 677-686Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiw561
Keywords
Tuberculosis meningitis; HIV; microarray; inflammasomes; neutrophils
Categories
Funding
- Carnegie Corporation Training Award
- Discovery Foundation Academic Fellowship Award
- Perinatal HIV Research Unit, US Agency for International Development
- President's Emergency Plan for AIDS Relief
- Wellcome Trust [WT 097254, 081667, 084323, 097684, 104803, 098316]
- Fogarty International Center, National Institutes of Health [U2R TW007373-01A1, U2R TW007370-01A1]
- National Research Foundation of South Africa [96841, 85858, 64787]
- Francis Crick Institute [10126, 10218]
- UK Medical Research Council
- Wellcome Trust
- Cancer Research UK
- European & Developing Countries Clinical Trials Partnership [SP.2011.41304.074]
- South African Research Chairs Initiative of the Department of Science and Technology
- South African Medical Research Council through its TB and HIV Collaborating Centres Programme
- National Department of Health [RFA SAMRC-RFA-CC: TB/HIV/AIDS-01-2014]
- Medical Research Council [1105853, 1365570, MC_U117565642] Funding Source: researchfish
- The Francis Crick Institute [10218] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10126] Funding Source: researchfish
- Wellcome Trust [104803/Z/14/Z] Funding Source: researchfish
- MRC [MC_U117565642] Funding Source: UKRI
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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.
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