Background:Mycobacterium tuberculosis(M.tb), the causative bacterium of tuberculosis (TB), establishes residence and grows in human alveolar macrophages (AMs). Inter-individual variation inM.tb-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.Results:Herein, we systematically analyze interactions of a virulentM.tbstrain H37Rvwith 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 toM.tbinfection. Eigengene modules linkM.tbgrowth rate with host transcriptional and protein profiles at 24 and 72h. Systems analysis of differential RNA and protein expression identifies a robust network withIL1B,STAT1, andIDO1as hub genes associated withM.tbgrowth. 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.Conclusions:We observe large inter-individual differences in bacterial uptake and growth, with tenfold variation inM.tbload by 72h.The fine-scale resolution of this work enables the identification of genes and gene networks associated with earlyM.tbgrowth dynamics in defined donor clusters, an important step in developing potential biological indicators of individual susceptibility toM.tbinfection and response to therapies.