Human alveolar macrophage response to <i>Mycobacterium tuberculosis</i> : immune characteristics underlying large inter-individual variability

Abstract Mycobacterium tuberculosis ( M.tb ) establishes residence and growth in human alveolar macrophages (AMs). Large inter-individual variation in M.tb -AM interactions is a potential early indicator of TB risk and efficacy of therapies and vaccines. Herein, we systematically analyze interactions of a virulent M.tb strain with freshly isolated human AMs from 28 healthy adult donors, measuring host RNA expression and secreted candidate proteins associated with TB pathogenesis over 72h. We observe large inter-individual differences in bacterial uptake and growth, with tenfold variation in M.tb load at 72h, reflected by large variation of gene expression programs. Systems analysis of differential and variable RNA and protein expression identifies TB-associated genes and networks ( e.g., IL1B and IDO1 ). RNA time profiles document early stimulation of M1-type macrophage gene expression followed by emergence of an M2-type profile. The fine-scale resolution of this work enables the separation of genes and networks regulating early M.tb growth dynamics, and development of potential markers of individual susceptibility to M.tb infection and response to therapies.