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Clinical outcomes reflect complex host-pathogen interactions. Epidemiological and animal studies have suggested influenza coinfection as a risk factor for progression from contained infection to active disease, but human studies have been lacking. Using a whole blood luminescent mycobacterial growth inhibition assay within a human influenza challenge study, we show that influenza infection reduces immunological control of mycobacterial growth. Transcriptome-wide RNA sequencing, cytokine and cellular analyses of subjects\u2019 blood before and after influenza infection reveal that innate immune pathways, including type 1 interferon signalling, are activated by influenza but their subsequent responsiveness to mycobacteria is reduced, with multiple genes\u2019 responses to BCG\n                    <jats:italic>lux<\/jats:italic>\n                    infection repressed by influenza coinfection. Our data suggest that influenza infection impairs immune mechanisms that contain mycobacterial growth and may be a risk factor for tuberculosis (TB) disease. 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