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

<title>Abstract</title> <bold>Background: </bold><italic>Mycobacterium tuberculosis</italic> (<italic>M.tb)</italic>, the causative bacterium of tuberculosis (TB), establishes residence and grows in human alveolar macrophages (AMs). Inter-individual variation in<italic> M.tb</italic>-human AM interactions can indicate TB risk and the efficacy of therapies and vaccines; however, we currently lack an understanding of the gene and protein expression programs that dictate this variation in the lungs. <bold>Results: </bold>Herein, we systematically analyze interactions of a virulent <italic>M.tb </italic>strain H₃₇R_vwith freshly isolated human AMs from 28 healthy adult donors, measuring host RNA expression and secreted candidate proteins associated with TB pathogenesis over 72h. A large set of genes possessing highly variable inter-individual expression levels are differentially expressed in response to <italic>M.tb </italic>infection<italic>.</italic> Eigengene modules link <italic>M.tb</italic> growth rate with host transcriptional and protein profiles at 24 and 72h. Systems analysis of differential RNA and protein expression identifies a robust network with <italic>IL1B</italic>, <italic>STAT1</italic>, and <italic>IDO1</italic> as hub genes associated with <italic>M.tb</italic> growth. RNA time profiles document stimulation towards an M1-type macrophage gene expression followed by emergence of an M2-type profile. Finally, we replicate these results in a cohort from a TB-endemic region, finding a substantial portion of significant differentially expressed genes overlapping between studies. <bold>Conclusions: </bold>We observe large inter-individual differences in bacterial uptake and growth, with tenfold variation in <italic>M.tb </italic>load by 72h.The fine-scale resolution of this work enables the identification of genes and gene networks associated with early <italic>M.tb</italic> growth dynamics in defined donor clusters, an important step in developing potential biological indicators of individual susceptibility to <italic>M.tb </italic>infection and response to therapies.