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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antiretroviral Therapy, Highly Active / adverse effects
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspases / genetics
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Caspases / immunology
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Cytokines / genetics
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Cytokines / immunology*
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Female
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Gene Expression Profiling
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HIV Infections / complications
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HIV Infections / drug therapy
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HIV Infections / immunology*
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Humans
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Immune Reconstitution Inflammatory Syndrome / chemically induced
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Immune Reconstitution Inflammatory Syndrome / genetics
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Immune Reconstitution Inflammatory Syndrome / immunology*
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Inflammasomes / genetics
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Inflammasomes / immunology*
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Inflammation Mediators
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Interleukin-1 / genetics
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Interleukin-1 / immunology
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Leukocytes, Mononuclear / immunology
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Male
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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Receptors, Interleukin-1 / antagonists & inhibitors
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Receptors, Interleukin-1 / immunology
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Toll-Like Receptors / genetics
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Toll-Like Receptors / immunology*
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Triggering Receptor Expressed on Myeloid Cells-1
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Tuberculosis / complications
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Tuberculosis / immunology*
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Young Adult
Substances
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Cytokines
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Inflammasomes
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Inflammation Mediators
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Interleukin-1
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Membrane Glycoproteins
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Receptors, Immunologic
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Receptors, Interleukin-1
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TIRAP protein, human
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TREM1 protein, human
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Toll-Like Receptors
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Triggering Receptor Expressed on Myeloid Cells-1
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CASP5 protein, human
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Caspases
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Caspase 1