Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens

Abstract

Manganese (Mn) and Zinc (Zn) are essential micronutrients whose concentration and location within cells are tightly regulated at the onset of infection. Two families of Zn transporters (ZIPs and ZnTs) are largely responsible for regulation of cytosolic Zn levels and to a certain extent, Mn levels, although much less is known regarding Mn. The capacity of pathogens to persevere also depends on access to micronutrients, yet a fundamental gap in knowledge remains regarding the importance of metal exchange at the host interface, often referred to as nutritional immunity. ZIP8, one of 14 ZIPs, is a pivotal importer of both Zn and Mn, yet much remains to be known. Dietary Zn deficiency is common and commonly occurring polymorphic variants of ZIP8 that decrease cellular metal uptake (Zn and Mn), are associated with increased susceptibility to infection. Strikingly, ZIP8 is the only Zn transporter that is highly induced following bacterial exposure in key immune cells involved with host defense against leading pathogens. We postulate that mobilization of Zn and Mn into key cells orchestrates the innate immune response through regulation of fundamental defense mechanisms that include phagocytosis, signal transduction, and production of soluble host defense factors including cytokines and chemokines. New evidence also suggests that host metal uptake may have long-term consequences by influencing the adaptive immune response. Given that activation of ZIP8 expression by pathogens has been shown to influence parenchymal, myeloid, and lymphoid cells, the impact applies to all mucosal surfaces and tissue compartments that are vulnerable to infection. We also predict that perturbations in metal homeostasis, either genetic- or dietary-induced, has the potential to impact bacterial communities in the host thereby adversely impacting microbiome composition. This review will focus on Zn and Mn transport via ZIP8, and how this vital metal transporter serves as a "go to" conductor of metal uptake that bolsters host defense against pathogens. We will also leverage past studies to underscore areas for future research to better understand the Zn-, Mn- and ZIP8-dependent host response to infection to foster new micronutrient-based intervention strategies to improve our ability to prevent or treat commonly occurring infectious disease.

Keywords: host defense; infection. (Min. 5-Max. 8); manganese; zinc; zinc transporter.

FIGURE 1

Comparison of the roles of zinc and manganese in immune-mediated host defence against infection. Zn deficiency is common worldwide and physiological Zn concentrations protect against infections by: triggering a variety of transcription factors involved in the immune response, preventing apoptosis of B cells and inhibiting the NF-κB pathway following intracellular transcript via ZIP8. In contrast Mn deficiency is rare and it helps protect against infection but different mechanisms that include acting as cofactor for glycosyltransferase enzymes essential for post translational protein glycosylation, enhancing apoptosis of B cells and activating the NF-κB pathway. Whereas each metal has contrasting and distinct functions, they both have antioxidant properties and help facilitate T cell receptor (TCR) signalling. Stars indicate the common polymorphic variants of ZIP8. Red arrows indicate inhibition, black arrows indicate activation.