Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis

Abstract

Transition metal ions are essential micronutrients for all living organisms. In mammals, these ions are often protein-bound and sequestered within cells, limiting their availability to microbes. Moreover, in response to infection, mammalian hosts further reduce the availability of metal nutrients by activating epithelial cells and recruiting neutrophils, both of which release metal-binding proteins with antimicrobial function. Microorganisms, in turn, have evolved sophisticated systems to overcome these limitations and acquire the metal ions essential for their growth. Here we review some of the mechanisms employed by the host and by pathogenic microorganisms to compete for transition metal ions, with a discussion of how evading "nutritional immunity" benefits pathogens. Furthermore, we provide new insights on the mechanisms of host-microbe competition for metal ions in the mucosa, particularly in the inflamed gut.

Keywords: S100 proteins; calprotectin; infection; iron; lipocalin-2; manganese; nutritional immunity; zinc.

Figure 1

A battle for metals in the intestinal mucosa: mechanisms of host metal sequestration and microbial metal acquisition. To limit microbial growth, the mammalian host sequesters free iron, zinc, and manganese ions by expressing proteins in the mucosa that directly bind metals or metal-binding agents in a process termed nutritional immunity. Lactoferrin binds to iron (Fe) and calprotectin binds to zinc (Zn) and manganese (Mn). Hemopexin can limit the amount of circulating iron-bound heme (He) and lipocalin-2 sequesters the bacterial iron-scavenging siderophore enterobactin. Upon infection, inflammatory mediators increase the expression of metal-sequestering proteins, which is detrimental to microbes lacking mechanisms to survive metal deprivation. Inflammatory cytokines, IL-17 and IL-22, produced by T cells induce epithelial cells to express antimicrobial proteins including lipocalin-2 and calprotectin. Furthermore, activated epithelial cells secrete CXC chemokines that recruit neutrophils to the site of infection; neutrophils also express high levels of lactoferrin, lipocalin-2, and calprotectin. Microbial infection and inflammation can stimulate the production of hepcidin in the liver and in macrophages, which further reduces iron availability by inducing the degradation of the cellular iron exporter ferroportin 1. In addition, the divalent metal ion transporter NRAMP1 can export manganese and iron out of the macrophage phagosome to further restrict metal availability to intracellular pathogens. To overcome metal starvation, pathogens (red ovals) employ several strategies to acquire iron, zinc and manganese. Highly specialized ABC-type transporters facilitate the uptake of zinc and manganese as well as iron bound to heme and siderophores. Siderophores, such as enterobactin, are iron-scavenging agents. Although lipocalin-2 can sequester enterobactin to limit microbial access to iron, some pathogens use salmochelin, a C-glucosylated derivative of enterobactin that cannot be bound by lipocalin-2. Some pathogens also express NRAMP family transporters and ZIP family transporters for the uptake of manganese and zinc.