Nutritional immunity beyond iron: a role for manganese and zinc

Abstract

Vertebrates sequester iron from invading pathogens, and conversely, pathogens express a variety of factors to steal iron from the host. Recent work has demonstrated that in addition to iron, vertebrates sequester zinc and manganese both intracellularly and extracellularly to protect against infection. Intracellularly, vertebrates utilize the ZIP/ZnT families of transporters to manipulate zinc levels, as well as Nramp1 to manipulate manganese levels. Extracellularly, the S100 protein calprotectin sequesters manganese and potentially zinc to inhibit microbial growth. To circumvent these defenses, bacteria possess high affinity transporters to import specific nutrient metals. Limiting the availability of zinc and manganese as a mechanism to defend against infection expands the spectrum of nutritional immunity and further establishes metal sequestration as a key defense against microbial invaders.

Figure 1. Zinc and manganese are found at reduced levels at localized sites of infection as compared to surrounding healthy tissues

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) of S. aureus infected organs from wild-type and calprotectin-deficient mice. Top panel shows hematoxylin-eosin stains of S. aureus infected livers. Bottom panels show LA-ICP-MS analysis maps for Ca²⁺ (calcium-44), Mn²⁺ (manganese-55), and Zn²⁺ (zinc-67). Arrows denote the site of abscesses. Scales are presented in arbitrary units. Adapted from Corbin et. al. [10]

Figure 2. The battle for nutrient metal at the host pathogen interface

Based on available literature, the following represents a working model describing the competition for non-iron metals between vertebrates and bacterial pathogens. (A) Keratinocytes express the antimicrobial compounds S100A7 and S100A15 to sequester metals and prevent infection. Following microbial infection, (B) the neutrophil proteins S100A8/S100A9 (calprotectin) and S100A12 bind manganese/zinc and copper/zinc, respectively. (C) Activated dendritic cells alter the expression of ZIP importers and ZnT exporters resulting in reduced cytoplasmic levels of zinc. ZIP8 is expressed by macrophages, dendritic cells, and T cells and results in decreased lysosomal zinc concentrations. Nramp1 is widely expressed by phagocytic cells and transports manganese out of the lysosome. (D) To compete with host-mediated zinc and manganese sequestration bacteria express high affinity metal transporters.