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

• DOI: 10.1038/ncomms9451
• Publication Date: 2015-09-24T09:07:45Z
• Authors: 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; Robert J. Wilkinson
• Keywords: Adult; Male; Inflammasomes; Mononuclear; 610; HIV Infections; INNATE; Article; NLRP3 INFLAMMASOME; ACTIVATION; Young Adult; 03 medical and health sciences; ANTIRETROVIRAL THERAPY; Immunologic; Immune Reconstitution Inflammatory Syndrome; Antiretroviral Therapy, Highly Active; Receptors; 616; Leukocytes; INTERLEUKIN-1; Tuberculosis; Humans; Highly Active; MACROPHAGES; Receptors, Immunologic; INFECTED PATIENTS; 0303 health sciences; Science & Technology; Membrane Glycoproteins; INTERFERON-GAMMA; Gene Expression Profiling; Caspase 1; Toll-Like Receptors; Immunity; Receptors, Interleukin-1; Triggering Receptor Expressed on Myeloid Cells-1; Immunity, Innate; 3. Good health; Multidisciplinary Sciences; Caspases; Leukocytes, Mononuclear; Science & Technology - Other Topics; Cytokines; Female; MYCOBACTERIUM-TUBERCULOSIS; Inflammation Mediators; RESPONSES; Interleukin-1

AbstractPatients 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.