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

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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
    Imperial College London, London W2 1PG, UK)

  • Katalin A. Wilkinson

    (The Francis Crick Institute Mill Hill Laboratory
    Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa)

  • 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
    National Heart and Lung Institute, Imperial College London)

  • Robert J. Wilkinson

    (The Francis Crick Institute Mill Hill Laboratory
    Clinical Infectious Diseases Research Initiative, University of Cape Town, Anzio Road, Observatory 7925, South Africa
    Imperial College London, London W2 1PG, UK)

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.

Suggested Citation

  • 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 Angui, 2015. "HIV–tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling," Nature Communications, Nature, vol. 6(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9451
    DOI: 10.1038/ncomms9451
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