Nutritional immunity: transition metals at the pathogen–host interface

Key Points

  • Microbial pathogens require nutrient metals in order to grow and cause disease. However, excess metals are toxic, so metal levels must be tightly regulated during infection. Vertebrates have evolved to exploit this metal dependence and metal toxicity through strategies that either prevent access to nutrient metal or direct excess metals towards invading pathogens. Collectively, these processes are known as nutritional immunity.

  • The struggle between host and pathogen for nutrient metals is best studied in the area of Fe. Fe is sequestered from invading pathogens either intracellularly or in high-affinity Fe-binding proteins. To combat host-mediated Fe sequestration, microbial pathogens elaborate several high-affinity Fe acquisition systems.

  • Recently, vertebrate proteins of the innate immune system have been identified that prevent microbial infection through the chelation of nutrient Mn and Zn. These proteins are members of the S100 family of Ca-binding proteins and are abundant at sites of inflammation. In addition to Mn and Zn sequestration, vertebrates can use strategies to direct toxic levels of Mn and Zn towards microbial pathogens. Bacterial measures to combat Mn and Zn sequestration, as well as the toxicity that is associated with excess levels of these metals, are beginning to be uncovered.

  • It is becoming increasingly evident that host-mediated direction of excess Cu towards microbial pathogens is a crucial aspect of vertebrate defence against infection. This observation has provided an explanation for the broad conservation of Cu detoxification systems across disease-causing microorganisms.

  • The importance of nutritional immunity for defence against infection is highlighted by the observation that inherited defects in transition metal homeostasis dramatically affect host susceptibility to certain infectious diseases. This fact underscores the tremendous therapeutic potential of targeting bacterial metal acquisition systems.

Abstract

Transition metals occupy an essential niche in biological systems. Their electrostatic properties stabilize substrates or reaction intermediates in the active sites of enzymes, and their heightened reactivity is harnessed for catalysis. However, this heightened activity also renders transition metals toxic at high concentrations. Bacteria, like all living organisms, must regulate their intracellular levels of these elements to satisfy their physiological needs while avoiding harm. It is therefore not surprising that the host capitalizes on both the essentiality and toxicity of transition metals to defend against bacterial invaders. This Review discusses established and emerging paradigms in nutrient metal homeostasis at the pathogen–host interface.

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Figure 1: Fe limitation during bacterial infections.
Figure 2: Fe acquisition during bacterial infections.
Figure 3: Mn2+ and Zn2+ chelation by the host.
Figure 4: Mn2+ and Zn2+ homeostasis in the pathogen.
Figure 5: New insights into the roles for Cu+ in innate immunity.

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Acknowledgements

The authors thank members of the Skaar laboratory for critical reading of the manuscript. Work in the Skaar laboratory is supported by grants AI091771, AI069233 and AI073843 from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. E.P.S. is a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Diseases. M.I.H. was supported by a Howard Hughes International Student Fellowship.

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Glossary

Transition metals

Elements that are in groups 3–12 of the periodic table, have an incomplete inner (penultimate) electron shell and can therefore exhibit multiple valences.

Protoporphyrin

A tetrapyrole ring containing two vinyl, four methyl and two propionic acid side chains encircling a metal ion. In the case of haem, the tetrapyrrole ring encircles a singular Fe2+ atom.

Haptoglobin

A serum protein that binds free haemoglobin and inhibits its oxidative activity.

Haemopexin

A haem-scavenging protein that is found in serum and binds haem with high affinity.

Natural resistance-associated macrophage protein 1

A divalent cation transporter that is expressed on the phagosomal membrane.

Biliverdin

A green pigment that is a product of enzymatic haem catabolism.

Staphylobilin

A product of haem catabolism; this molecule is produced by the IsdG family of haem oxygenases.

SH3 domain protein

Proteins containing the SRC homology 3 (SH3) domain, which consists of five or six β-strands arranged as two tightly packed β-sheets. This domain typically mediates protein–protein interactions by binding to proline-rich regions on the binding partner.

Fe–S clusters

Complexes of Fe and bridging sulphides. Fe–S clusters are often found in metalloproteins and have structural or functional roles in proteins, most notably in electron transfer reactions and redox sensing.

Rhizosphere

The zone immediately surrounding the plant root; in this zone, biological and chemical interactions occur among the plant, the soil itself and soil microorganisms.

Superoxide dismutase

An enzyme that catalyses the formation of hydrogen peroxide from superoxide.

Pyochelin

A siderophore that is produced by Pseudomonas spp. and binds Fe3+ and some other metal ions with high affinity.

P type ATPases

A class of autocatalytic ATP-hydrolysing transporters that is found in bacteria, archaea and eukaryotes. Most members of this class transport cations.

RND family transporters

Efflux transporters that span the inner and outer membranes of Gram-negative bacteria. These transporters harness the proton gradient at the inner membrane to drive substrate efflux from the cytosol to the extracellular environment.

Fenton chemistry

The Fe2+-catalysed production of hydroxyl radicals from hydrogen peroxide: Fe2++H2O2→Fe3++OH+OH.

Haemochromatosis

A condition of Fe overload that can result from a primary defect in Fe absorption or storage, or that can occur secondarily to medical procedures such as blood transfusions.

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Hood, M., Skaar, E. Nutritional immunity: transition metals at the pathogen–host interface. Nat Rev Microbiol 10, 525–537 (2012). https://doi.org/10.1038/nrmicro2836

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