Bell, Liam Peyper, Janique M Garnett, Shaun Tadokera, Rabecca Wilkinson, Robert Meintjes, Graeme Blackburn, Jonathan M TB-IRIS: Proteomic analysis of in vitro PBMC responses to Mycobacterium tuberculosis and response modulation by dexamethasone 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. Anti-retroviral therapy;Human peripheral blood mononuclear cells;Mass spectrometry;Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome;Proteomics;Tuberculosis-HIV co-infection;Anti-Retroviral Agents;Chromatography, Liquid;Coinfection;Dexamethasone;Female;Gene Expression Regulation;HIV Infections;Humans;Immune Reconstitution Inflammatory Syndrome;Leukocytes, Mononuclear;Male;Mycobacterium tuberculosis;Prospective Studies;Proteome;South Africa;Tandem Mass Spectrometry;Tuberculosis;Wilkinson, R FC001218;Oncology & Carcinogenesis;1103 Clinical Sciences 2020-07-15
    https://crick.figshare.com/articles/journal_contribution/TB-IRIS_Proteomic_analysis_of_in_vitro_PBMC_responses_to_Mycobacterium_tuberculosis_and_response_modulation_by_dexamethasone/12624122