Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis—the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl−/− macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between antibacterial and antiviral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map for developing a deeper understanding of the intricate interactions between Mtb and its host. Display omitted •Creation of a Mtb-host protein-protein interaction map using mass spectrometry•LpqN is a novel Mtb virulence factor that associates with CBL, a host ubiquitin ligase•Removal of CBL rescues the attenuated lpqN Mtb mutant•CBL acts as a switch between antiviral and antibacterial responses in host Penn et al. used an affinity tag purification mass spectrometry approach to generate an Mtb-human protein-protein interaction map, uncovering a connection between LpqN, a virulence factor in Mtb, and CBL, a host ubiquitin ligase. CBL suppresses lpqN attenuation and acts as a switch for host antibacterial and antiviral responses.