An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses

Mol Cell. 2018 Aug 16;71(4):637-648.e5. doi: 10.1016/j.molcel.2018.07.010.


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.

Keywords: Cbl; LpqN; host-pathogen interaction; macrophage; mycobacterium; protein-protein interaction; tuberculosis; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / immunology
  • Cell Line, Tumor
  • Chlamydia trachomatis / genetics
  • Chlamydia trachomatis / immunology
  • Gene Expression Regulation
  • HIV / genetics*
  • HIV / immunology
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / immunology
  • Host-Pathogen Interactions*
  • Humans
  • Lymphocytes / microbiology
  • Lymphocytes / virology
  • Macrophages / microbiology
  • Macrophages / virology
  • Mice
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / immunology
  • Primary Cell Culture
  • Protein Binding
  • Protein Interaction Mapping
  • Proto-Oncogene Proteins c-cbl / deficiency
  • Proto-Oncogene Proteins c-cbl / genetics*
  • Proto-Oncogene Proteins c-cbl / immunology
  • RAW 264.7 Cells
  • Signal Transduction
  • Virulence Factors / genetics*
  • Virulence Factors / immunology


  • Bacterial Proteins
  • Virulence Factors
  • Proto-Oncogene Proteins c-cbl
  • CBL protein, human