Salmonella -Driven Polarization of Granuloma Macrophages Counteracts TNF-Mediated Pathogen Restriction During Persistent Infection

Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas comprised of macrophages. Granuloma macrophages exhibit heterogeneous polarized 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 in vivo. We show that STm persists within splenic granulomas that are predominated by CD11b+CD11c+Ly6C+ macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the virulence factor 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. Strikingly, in mice infected with ∆steE mutant STm, TNF signaling becomes dispensable for limiting M2 granuloma macrophages and pathogen persistence. Thus, manipulation of granuloma macrophage polarization represents a crucial pathogenesis strategy for intracellular bacteria to overcome host restriction during persistent infection.