1. HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.
- Author
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Lai RPJ, Meintjes G, Wilkinson KA, Graham CM, Marais S, Van der Plas H, Deffur A, Schutz C, Bloom C, Munagala I, Anguiano E, Goliath R, Maartens G, Banchereau J, Chaussabel D, O'Garra A, and Wilkinson RJ
- Subjects
- Adult, Antiretroviral Therapy, Highly Active adverse effects, Caspase 1 genetics, Caspase 1 immunology, Caspases genetics, Caspases immunology, Cytokines genetics, Female, Gene Expression Profiling, HIV Infections complications, HIV Infections drug therapy, Humans, Immune Reconstitution Inflammatory Syndrome chemically induced, Immune Reconstitution Inflammatory Syndrome genetics, Immunity, Innate genetics, Immunity, Innate immunology, Inflammasomes genetics, Inflammation Mediators, Interleukin-1 genetics, Interleukin-1 immunology, Leukocytes, Mononuclear immunology, Male, Membrane Glycoproteins antagonists & inhibitors, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Receptors, Immunologic genetics, Receptors, Immunologic immunology, Receptors, Interleukin-1 antagonists & inhibitors, Receptors, Interleukin-1 immunology, Toll-Like Receptors genetics, Triggering Receptor Expressed on Myeloid Cells-1, Tuberculosis complications, Young Adult, Cytokines immunology, HIV Infections immunology, Immune Reconstitution Inflammatory Syndrome immunology, Inflammasomes immunology, Toll-Like Receptors immunology, Tuberculosis immunology
- 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.
- Published
- 2015
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