HIV–tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling

Rachel P. J. Lai, Graeme Meintjes (), Katalin A. Wilkinson, Christine M. Graham, Suzaan Marais, Helen Van der Plas, Armin Deffur, Charlotte Schutz, Chloe Bloom, Indira Munagala, Esperanza Anguiano, Rene Goliath, Gary Maartens, Jacques Banchereau, Damien Chaussabel, Anne O’Garra and Robert J. Wilkinson
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Rachel P. J. Lai: The Francis Crick Institute Mill Hill Laboratory
Graeme Meintjes: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Katalin A. Wilkinson: The Francis Crick Institute Mill Hill Laboratory
Christine M. Graham: The Francis Crick Institute Mill Hill Laboratory
Suzaan Marais: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Helen Van der Plas: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Armin Deffur: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Charlotte Schutz: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Chloe Bloom: The Francis Crick Institute Mill Hill Laboratory
Indira Munagala: Baylor Institute for Immunology Research
Esperanza Anguiano: Baylor Institute for Immunology Research
Rene Goliath: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Gary Maartens: Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Jacques Banchereau: Baylor Institute for Immunology Research
Damien Chaussabel: Systems Immunology, Benaroya Research Institute
Anne O’Garra: The Francis Crick Institute Mill Hill Laboratory
Robert J. Wilkinson: The Francis Crick Institute Mill Hill Laboratory

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

Date: 2015
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DOI: 10.1038/ncomms9451

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