Salmonella-Driven Polarization of Granuloma Macrophages Antagonizes TNF-Mediated Pathogen Restriction during Persistent Infection

Cell Host Microbe. 2020 Jan 8;27(1):54-67.e5. doi: 10.1016/j.chom.2019.11.011. Epub 2019 Dec 26.


Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium (STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b+CD11c+Ly6C+ macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.

Keywords: SPI-2; Salmonella; SarA; SteE; TNF; alternatively activated; granuloma; macrophage polarization; persistent infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism
  • Granuloma / immunology*
  • Granuloma / microbiology
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Interleukin-4 / metabolism
  • Macrophage Activation / immunology*
  • Macrophages / microbiology
  • Mice
  • Salmonella Infections / immunology*
  • Salmonella typhimurium / immunology
  • Salmonella typhimurium / metabolism
  • Salmonella typhimurium / pathogenicity
  • Spleen / cytology
  • Spleen / microbiology
  • Spleen / pathology
  • Trans-Activators / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Virulence Factors / metabolism


  • Bacterial Proteins
  • SarA protein, bacterial
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Virulence Factors
  • Interleukin-4