Metal Micronutrients

Zinc (Zn) is an essential micronutrient whose concentration and location within cells is tightly regulated by Zn transporters (ZIPs and ZnTs that increase and decrease cytosolic Zn levels, respectively). The capacity of M. tuberculosis (M.tb) to persevere in the macrophage phagosome depends in part on access to micronutrients yet there is a fundamental gap in knowledge regarding the importance of Zn at the M.tb-host interface. Resolving this gap is critical since dietary Zn deficiency and polymorphic variants of ZIP8 are associated with increased susceptibility to TB and other infectious diseases. Our data indicate that ZIP8 is the only Zn transporter highly induced following M.tb infection of human macrophages and is enriched at the M.tb phagosome (Pyle et al Int J Mol Sci 2017). We seek to understand the impact of zinc transporters and zinc homeostasis on TB, which is expected to foster new micronutrient-based intervention strategies to improve TB prevention and treatment.

Selected Publications

  • Pyle, Charlie J, Abul K Azad, Audrey C Papp, Wolfgang Sadee, Daren L Knoell, and Larry S Schlesinger. (2017) 2017. “Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium Tuberculosis.”. International Journal of Molecular Sciences 18 (11). https://doi.org/10.3390/ijms18112375.
    Publisher's Version

    Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world's most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial metal metabolism, and bacterial survival. The manipulation of micronutrients is a critical mechanism of host defense against infection. In particular, the human zinc transporter Zrt-/Irt-like protein 8 (ZIP8), one of 14 ZIP family members, is important in the flux of divalent cations, including zinc, into the cytoplasm of macrophages. It also has been observed to exist on the membrane of cellular organelles, where it can serve as an efflux pump that transports zinc into the cytosol. ZIP8 is highly inducible in response to M.tb infection of macrophages, and we have observed its localization to the M.tb phagosome. The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. In particular, given the importance of zinc as an essential nutrient required for humans and M.tb, it is not yet clear whether ZIP-guided zinc transport serves as a host protective factor or, rather, is targeted by M.tb to enable its phagosomal survival.