title: TB-IRIS: Proteomic analysis of in vitro PBMC responses to Mycobacterium tuberculosis and response modulation by dexamethasone.
abstract: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) occurs in 8-54% of South African patients undergoing treatment for tuberculosis/human immunodeficiency virus co-infection. Improved TB-IRIS molecular pathogenesis understanding would enhance risk stratification, diagnosis, prognostication, and treatment. We assessed how TB-IRIS status and dexamethasone influence leukocyte proteomic responses to Mycobacterium tuberculosis (Mtb). Patient blood was obtained three weeks post-anti-retroviral therapy initiation. Isolated mononuclear cells were stimulated ex vivo with heat-killed Mtb in the presence/absence of dexamethasone. Mass spectrometry-based proteomic comparison of TB-IRIS and non-IRIS patient-derived cells facilitated generation of hypotheses regarding pathogenesis. Few represented TB-IRIS-group immune-related pathways achieved significant activation, with relative under-utilisation of "inter-cellular interaction" and "Fcγ receptor-mediated phagocytosis" (but a tendency towards apoptosis-related) pathways. Dexamethasone facilitated significant activation of innate-related pathways. Differentially-expressed non-IRIS-group proteins suggest focused and co-ordinated immunological pathways, regardless of dexamethasone status. Findings suggest a relative deficit in TB-IRIS-group responses to and clearance of Mtb antigens, ameliorated by dexamethasone.
authors.affiliation: Department of Integrative Biomedical Sciences & Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa; Centre for Proteomic and Genomic Research (CPGR), Observatory, 7925 Cape Town, South Africa.
authors.forename: Liam
authors.initials: L
authors.lastname: Bell
authors.affiliation: Department of Integrative Biomedical Sciences & Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa.
authors.forename: Janique M
authors.initials: JM
authors.lastname: Peyper
authors.affiliation: Department of Integrative Biomedical Sciences & Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa.
authors.forename: Shaun
authors.initials: S
authors.lastname: Garnett
authors.affiliation: Department of Integrative Biomedical Sciences & Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa; Clinical Infectious Diseases Research Initiative, IDM, University of Cape Town, Observatory, 7925 South Africa; HIV/AIDS, STIs and TB Programme, Human Sciences Research Council, Arcadia, 0002 Pretoria, South Africa.
authors.forename: Rabecca
authors.initials: R
authors.lastname: Tadokera
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, UK; Clinical Infectious Diseases Research Initiative, IDM, University of Cape Town, Observatory, 7925 South Africa; Department of Medicine, University of Cape Town, Observatory, 7925 South Africa; Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Wilkinson
authors.affiliation: Clinical Infectious Diseases Research Initiative, IDM, University of Cape Town, Observatory, 7925 South Africa; Department of Medicine, University of Cape Town, Observatory, 7925 South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Department of Integrative Biomedical Sciences & Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, South Africa. Electronic address: jonathan.blackburn@uct.ac.za.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blackburn
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D002853:Chromatography, Liquid; D060085:Coinfection / Q000188:drug therapy; D003907:Dexamethasone / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000382:microbiology; D008297:Male; D009169:Mycobacterium tuberculosis; D011446:Prospective Studies; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D013019:South Africa; D053719:Tandem Mass Spectrometry; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D044966:Anti-Retroviral Agents; D020543:Proteome; D003907:Dexamethasone
keywords: Anti-retroviral therapy; Human peripheral blood mononuclear cells; Mass spectrometry; Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome; Proteomics; Tuberculosis-HIV co-infection