Iron and zinc exploitation during bacterial pathogenesis

Abstract

Ancient bacteria originated from metal-rich environments. Billions of years of evolution directed these tiny single cell creatures to exploit the versatile properties of metals in catalyzing chemical reactions and biological responses. The result is an entire metallome of proteins that use metal co-factors to facilitate key cellular process that range from the production of energy to the replication of DNA. Two key metals in this regard are iron and zinc, both abundant on Earth but not readily accessible in a human host. Instead, pathogenic bacteria must employ clever ways to acquire these metals. In this review we describe the many elegant ways these bacteria mine, regulate, and craft the use of two key metals (iron and zinc) to build a virulence arsenal that challenges even the most sophisticated immune response.

Figure 1. Bacterial iron uptake in the host

Under normal conditions, commensal bacteria of the GI tract use siderophore-based iron uptake systems to obtain iron. Upon infection, the host uses nutritional immunity to restrict bacterial access to essential nutrients including iron (top panel). Host iron limitation includes hepcidin- mediated reduction of circulatory iron and/or the production of NGAL to prevent siderophores from chelating free iron. Additionally, iron is kept unavailable for bacteria by being bound to heme or proteins such as transferrin or ferritin. Bacterial pathogens employ diverse strategies to counter nutritional immunity (bottom panel), including the utilization of transferrin/lactoferrin, heme/heme-containing proteins, iron storage proteins such as ferritin, blocking the host from recognizing their siderophores, utilizing other species siderophores, and even invading into the cytoplasm of host cells.

Figure 2. The role of zinc in bacterial pathogenesis

A. Bacterial pathogens encounter higher concentrations of zinc at epithelial surfaces, where lysed cells release metallothioneins that liberate zinc upon oxidative stress. To combat Zn²⁺ toxicity, bacteria employ efflux transporters like RND, ZnT and Pit. ZUR proteins are bound to bacterial DNA and prevent transcription of zinc uptake mechanisms. Metalloproteases cleave mucins, glycoproteins, and tight cell junctions to allow bacteria to translocate into other tissues. B. At sites of infection and translocation, the host can reduce available zinc by secreting the zinc chelator calprotectin. Once in zinc deficient environments, bacterial ZUR proteins relieve transcriptional repression and zinc uptake mechanisms are expressed, such as the Znu ABC transporter. Here, metalloproteases can cleave collagen, cytokine receptors, cytokines and immunoglobulins to further disrupt tissues and interfere with immune signaling. C. When present in the bloodstream, host α-2-macroglobulin can inactivate metalloproteases via entrapment. However, metalloproteases can cleave fibrinogen, prothrombin, and factor X to disrupt the clotting cascade and permit further dissemination.