title: HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.
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.
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.
authors.forename: Rachel P J
authors.initials: RPJ
authors.lastname: Lai
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.|Department of Medicine, Imperial College London, London W2 1PG, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.|Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Graham
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Suzaan
authors.initials: S
authors.lastname: Marais
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: Van der Plas
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Armin
authors.initials: A
authors.lastname: Deffur
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.
authors.forename: Chloe
authors.initials: C
authors.lastname: Bloom
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA.
authors.forename: Indira
authors.initials: I
authors.lastname: Munagala
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Anguiano
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Rene
authors.initials: R
authors.lastname: Goliath
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Banchereau
authors.affiliation: Systems Immunology, Benaroya Research Institute, Seattle, Washington 98101, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.|Department of Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.|Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Anzio Road, Observatory 7925, South Africa.|Department of Medicine, Imperial College London, London W2 1PG, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C408842:TREM1 protein, human; D051193:Toll-Like Receptors; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C099217:CASP5 protein, human; D020169:Caspases; D020170:Caspase 1