Mycobacterium tuberculosis subverts macrophage-mediated defense through exploitation of the Zn transporter ZIP8

Zinc (Zn) is an essential micronutrient whose concentration and location are tightly regulated by Zn transporters. Mycobacterium tuberculosis (M.tb) resides in macrophage phagosomes, where it requires access to micronutrients, including Zn. Our data show that ZIP8 is the only Zn transporter in human macrophages highly induced by M.tb and is enriched at the M.tb phagosome. Using human and murine macrophages and mice deficient in ZIP8, we found that M.tb exploits ZIP8 to enhance its growth. ZIP8 imports Zn into the cytosol and out of the phagosome to subvert Zn poisoning. Cytosolic Zn dampens NF-κB activation and pro-inflammatory cytokine production while enhancing matrix metalloproteinase (MMP) production. Understanding the Zn- and ZIP8-dependent host response to M.tb infection is critical since dietary Zn deficiency and polymorphic ZIP8 variants are associated with increased susceptibility to tuberculosis and other infectious diseases.