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eSymposia | Tuberculosis: Science Aimed at Ending the Epidemic


Immunoproteomics & macrophage mechanisms of human resistance to TST/IGRA conversion


Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

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Immunoproteomics & macrophage mechanisms of human resistance to TST/IGRA conversion CM. Anterasian1*, JD. Simmons1, DL. Swaney2, GJ. Peterson1, P. Benchek3, P. Van1, R. Gottardo1, CM. Stein3, H. Mayanja-Kizza4, J. Johnson5, J. Cox2, NJ. Krogan6, WH. Boom3, TR. Hawn1; 1University of Washington; 2University of California, Berkeley; 3Case Western Reserve University; 4Makerere University, Kampala, Uganda; 5Icahn School of Medicine, Mount Sinai; 6University of California, San Francisco Background: Despite long-term and intense household exposure to Mycobacterium tuberculosis (Mtb), some individuals remain resistant to traditionally defined latent TB infection (LTBI) with persistently negative tuberculin skin tests and interferon-g release assays (“RSTR” phenotype). Global proteomics can be used to detect Mtb-induced changes in RSTR versus LTBI cellular biology, including pathways that are not transcriptionally regulated. We hypothesize that macrophage immunoproteomic responses to Mtb are genetically regulated and associated with Mtb clinical outcomes. Methods: Primary human monocyte-derived macrophages (MDMs) from Ugandan individuals (RSTR n=20, LTBI n=19) were infected ex vivo with Mtb H37Rv. Protein abundance was measured at 24 hours by mass spectrometry. Differentially abundant proteins (DAPs) in RSTR versus LTBI macrophages were identified using a linear mixed effects model incorporating age, sex, and kinship. Ugandan cohort transcriptomic data from Mtb-infected monocytes and genomic data from Illumina MegaEx array were used to identify DAP polymorphisms associated with DAP mRNA expression and cytokine mRNA expression. Results: We identified 46 DAPs that define the RSTR versus LTBI Mtb-induced proteome in MDMs (false-discovery rate (FDR) < 0.20). Enrichment analysis revealed vesicle-mediated transport (FDR

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