Iron at the host-microbe interface

Abstract

Iron is an essential micronutrient for nearly all living organisms. In addition to facilitating redox reactions, iron is bound by metalloproteins that participate in a variety of biological processes. As the bioavailability of free iron in host environments is extremely low, iron lies at the center of a battle for nutrients between microbes and their host. Mucosal surfaces such as the respiratory and gastrointestinal tracts are constantly exposed to commensal and pathogenic microorganisms. Whereas a key strategy of mammalian antimicrobial defense is to deprive microbes of iron, pathogens and some commensals have evolved effective strategies to circumvent iron limitation. Here we provide an overview of mechanisms underpinning the tug-of-war for iron between microbes and their host, with a particular focus on mucosal surfaces.

Introduction

Iron (Fe) is a vital micronutrient for nearly all forms of life, and is involved in critical physiological processes including oxygen transportation, energy metabolism, and DNA replication (Lieu et al., 2001). By existing primarily in two oxidation states, ferrous (Fe²⁺) and ferric (Fe³⁺) iron, this element has the flexibility to serve as a key cofactor in many enzymes as well as play a crucial role in facilitating a variety of redox reactions. Nevertheless, despite iron's essential roles in the beneficial chemistry of life, its redox potential can negatively impact biological molecules and cells; for example, the Fenton reaction involving Fe²⁺ and hydrogen peroxide yields reactive oxygen species (ROS) that can damage biomolecules including lipids, proteins, and DNA. Oxidative stress, in turn, is linked to aging, cardiovascular disorders, neurodegenerative diseases, and cancer (Liu et al., 2018). To minimize iron's reactivity and toxicity, the vast majority of iron in mammals is found in intracellular compartments, complexed with hemoproteins (e.g., hemoglobin, myoglobin), or the iron-storage protein ferritin (Lieu et al., 2001). Thus, the bioavailability of free iron is low in the mammalian environment, even during homeostasis. Moreover, in a process known as nutritional immunity, extracellular and intracellular iron is further decreased during infection to prevent the outgrowth of pathogens (Hood and Skaar, 2012). Successful pathogens have therefore evolved strategies to compete for and obtain iron from the host in order to replicate and thrive despite limited nutrient availability.

Mucosal surfaces constitute a physical barrier between the external environment and the inner body. During homeostasis, many of these surfaces are colonized by an assortment of microbes that are collectively referred to as the commensal microbiota, and typically include non-pathogenic bacteria, fungi, archaea, and viruses (Lozupone et al., 2012). Among the body sites with a commensal microbiota, the gastrointestinal (GI) tract, and in particular the colon, is home to the body's largest and most diverse microbial community. The host and its commensal microbiota have evolved a mutualistic interdependency that significantly contributes to many aspects of the host's normal physiology, ranging from metabolism, to resisting pathogen colonization (Dethlefsen et al., 2007), to shaping and maintaining the host's immune system (Belkaid and Hand, 2014). The host, in turn, provides its microbiota with nutrients and environments suitable for growth. Even so, not all microbes are able to colonize and/or flourish in a given host, as the availability of specific nutrients controls the abundance of certain microbes (Pereira and Berry, 2017). The ability to acquire and utilize nutrients is thus essential for commensal microbes to stably colonize their host.

Despite this coevolved mutualism, the mucosal immune system must still prevent microorganisms, be they commensals or pathogens, from disseminating beyond mucosal surfaces. On this front, iron sequestration by the host represents a conserved innate immune mechanism for limiting microbial growth. Nevertheless, pathogens have evolved strategies to circumvent these defenses. Here we provide an overview of mechanisms underpinning the tug-of-war for iron between microbes and their host, which ultimately determines the health of the host and the survival of pathogenic microbes.