The struggle for iron - a metal at the host-pathogen interface

Abstract

SummaryIron holds a central position at the host-pathogen interface because mammalian and microbial cells have an essential demand for the metal, which is required for many metabolic processes. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. While iron affects the secretion of cytokines and the activity of transcription factors orchestrating immune responses, immune cell-derived mediators and acute-phase proteins control both systemic and cellular iron homeostasis. Additionally, immune-mediated strategies aim at restricting the supply of the essential nutrient iron to pathogens, which represents an effective strategy of host defence. On the other hand, microbes have evoked multiple strategies to utilize iron because a sufficient supply of this metal is linked to pathogen proliferation, virulence and persistence. The control over iron homeostasis is a central battlefield in host-pathogen interplay influencing the course of an infectious disease in favour of either the mammalian host or the pathogenic invader. This review summarizes our current knowledge on the combat of host cells and pathogens for the essential nutrient iron focusing on the immune-regulatory roles of iron on cell-mediated immunity necessary to control intracellular microbes, the host's mechanisms of iron restriction and on the counter-acting iron-acquisition strategies employed by intracellular microbes.

Iron Regulatory Protein 1 Outcompetes Iron Regulatory Protein 2 in Regulating Cellular Iron Homeostasis in Response to Nitric Oxide

“…On the other hand, IRP1 activation by NO and the ensuing increase in the CIP could promote iron toxicity in inflammation-related pathologies, such as inflammatory bowel disease, Parkinson's disease, and acute lung injury (47,48) that are characterized by continuous production of reactive oxygen and nitrogen species. IRP1-mediated modulation of cellular iron metabolism by NO could also be important for macrophage cellular immune functions (49).…”

Tissue damage control in disease tolerance

“…Based on its relative abundance and ability to exchange electrons with a number of donor/acceptor molecules iron is at the center stage of many vital biological functions. Pathogens rely strictly on iron acquisition for the progression of infection, evolving strategies that fuel host iron into their own metabolic pathways 102 . It follows that host strategies that deny pathogen access to iron are a central and evolutionarily conserved host resistance mechanism 95,102,103 .…”

“…Pathogens rely strictly on iron acquisition for the progression of infection, evolving strategies that fuel host iron into their own metabolic pathways 102 . It follows that host strategies that deny pathogen access to iron are a central and evolutionarily conserved host resistance mechanism 95,102,103 . This defense strategy relies to a large extent on the expression of: i) hepcidin antimicrobial peptide gene (HAMP), a master regulator of systemic iron metabolic adaptation during infection that reduces iron acquisition from diet and suppresses iron cellular export 103 , ii) lipocalin-2, a soluble iron chelator encoded by the LCN2 gene that prevents extracellular pathogens from accessing iron 104 and iii) natural resistance associated macrophage protein function (NRAMP-1), an intracellular iron transporter encoded by the SLC11A1 gene, that removes iron from phagolysosomes and limits iron supply to intracellular pathogens 105 .…”

Blocking Yersiniabactin Import Attenuates Extraintestinal Pathogenic Escherichia coli in Cystitis and Pyelonephritis and Represents a Novel Target To Prevent Urinary Tract Infection

“…Iron is an essential cofactor for normal cell physiology, and bacteria require a source of iron to establish infection (9). Most tissues in the body limit iron availability to microorganisms, sequestering it in storage and carrier molecules such as transferrin, lactoferrin, and ferritin, or binding it to heme in hemoglobin and hemopexin (10). During infection, additional iron sequestration occurs as epithelial cells and neutrophils secrete lipocalin-2, a competitor for bacterial iron-scavenging siderophores, and iron absorption and recycling pathways are repressed (11).…”