Buried Treasure: Evolutionary Perspectives on Microbial Iron Piracy
Authors: Matthew F. Barber, Nels C. Elde
Journal: Trends in Genetics (2015)

The battle between microbes and their hosts for nutrient iron is emerging as a new front of evolutionary genetic conflict. Molecular arms races can emerge between host iron-binding proteins and microbial 'iron piracy' factors that steal this nutrient for growth. Such rapid evolution may also contribute to the host range of pathogenic microbes. Iron acquisition plays an important role in evolutionary interactions between microbes, both in the environment and within the host. Competition for iron can prevent infection by pathogens, while genetic changes in iron acquisition systems can enhance microbial virulence. Evolutionary conflicts for nutrient iron are revealing potential new genetic mechanisms of disease resistance as well as avenues for therapeutic development. Host–pathogen interactions provide valuable systems for the study of evolutionary genetics and natural selection. The sequestration of essential iron has emerged as a crucial innate defense system termed nutritional immunity, leading pathogens to evolve mechanisms of 'iron piracy' to scavenge this metal from host proteins. This battle for iron carries numerous consequences not only for host–pathogen evolution but also microbial community interactions. Here we highlight recent and potential future areas of investigation on the evolutionary implications of microbial iron piracy in relation to molecular arms races, host range, competition, and virulence. Applying evolutionary genetic approaches to the study of microbial iron acquisition could also provide new inroads for understanding and combating infectious disease. Host–pathogen interactions provide valuable systems for the study of evolutionary genetics and natural selection. The sequestration of essential iron has emerged as a crucial innate defense system termed nutritional immunity, leading pathogens to evolve mechanisms of 'iron piracy' to scavenge this metal from host proteins. This battle for iron carries numerous consequences not only for host–pathogen evolution but also microbial community interactions. Here we highlight recent and potential future areas of investigation on the evolutionary implications of microbial iron piracy in relation to molecular arms races, host range, competition, and virulence. Applying evolutionary genetic approaches to the study of microbial iron acquisition could also provide new inroads for understanding and combating infectious disease. The outcome of an infection can have profound consequences for both host and pathogen populations. Intense selective pressures make host–pathogen interactions an attractive biological model to study evolutionary genetics over relatively short intervals of time. To date, much work has focused on rapid evolution involving canonical host immune defenses or antibiotic resistance [1Daugherty M.D. Malik H.S. Rules of engagement: molecular insights from host–virus arms races.Annu. Rev. Genet. 2012; 46: 677-700Crossref PubMed Scopus (299) Google Scholar, 2Palmer A.C. Kishony R. Understanding, predicting and manipulating the genotypic evolution of antibiotic resistance.Nat. Rev. Genet. 2013; 14: 243-248Crossref PubMed Scopus (166) Google Scholar]. However, we now know that hosts possess numerous additional means to restrict pathogens, including factors engaged in other core physiological functions. Nutrient iron sequestration provides one such alternative mode of host defense against bacteria and eukaryotic pathogens [3Cassat J.E. Skaar E.P. Iron in infection and immunity.Cell Host Microbe. 2013; 13: 509-519Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar]. Iron is an essential micronutrient for microbes, as well as their hosts, due to its ability to readily shift between ferrous (Fe2+) and ferric (Fe3+) oxidative states for redox catalysis or electron transport. This ability to readily accept and donate electrons also makes iron highly volatile, necessitating a well-coordinated iron transport and storage system in metazoans to prevent the production of toxic free radicals [4Andrews N.C. Disorders of iron metabolism.N. Engl. J. Med. 1999; 341: 1986-1995Crossref PubMed Scopus (1497) Google Scholar]. The sequestration of free iron by host proteins simultaneously prevents acquisition by microbes, a protective effect termed nutritional immunity (see Glossary) [5Hood M.I. Skaar E.P. Nutritional immunity: transition metals at the pathogen–host interface.Nat. Rev. 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Adding to the fortuitous nature of their discovery, the authors posited that an iron-binding component present in the egg white prevented acquisition of this nutrient by microbes, which could have important implications for immunity. Two years later the scientists reported similar activity present in human blood serum [8Schade A.L. Caroline L. An iron-binding component in human blood plasma.Science. 1946; 104: 340-341Crossref Scopus (136) Google Scholar]. The factor responsible for this activity in both cases was later revealed to be the protein transferrin, which plays a central role in animal iron metabolism by binding and transporting this metal to target cells [9Ganz T. Nemeth E. Hepcidin and disorders of iron metabolism.Annu. Rev. Med. 2011; 62: 347-360Crossref PubMed Scopus (372) Google Scholar, 10Gkouvatsos K. et al.Regulation of iron transport and the role of transferrin.Biochim. Biophys. Acta. 2012; 1820: 188-202Crossref PubMed Scopus (290) Google Scholar]. 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Not only has transferrin been subject to strong positive selection in primates but also rapidly evolving sites almost entirely overlap with the binding interface of a bacterial surface receptor, transferrin-binding protein A (TbpA), an important virulence factor in several human pathogens including Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae, and Moraxella catarrhalis, as well as a number of agricultural pathogens (Figure 2A) [21Cornelissen C.N. et al.Gonococcal transferrin-binding protein 1 is required for transferrin utilization and is homologous to TonB-dependent outer membrane receptors.J. Bacteriol. 1992; 174: 5788-5797Crossref PubMed Scopus (180) Google Scholar, 37Schryvers A.B. Characterization of the human transferrin and lactoferrin receptors in Haemophilus influenzae.Mol. 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Many pathogens encode receptors for other host iron-binding proteins including lactoferrin, a transferrin paralog expressed in milk, saliva, tears, mucus, and the secondary granules of neutrophils [37Schryvers A.B. Characterization of the human transferrin and lactoferrin receptors in Haemophilus influenzae.Mol. Microbiol. 1988; 2: 467-472Crossref PubMed Scopus (42) Google Scholar, 42García-Montoya I.A. et al.Lactoferrin a multiple bioactive protein: an overview.Biochim. Biophys. Acta. 2012; 1820: 226-236Crossref PubMed Scopus (295) Google Scholar, 43Beddek A.J. Schryvers A.B. The lactoferrin receptor complex in Gram negative bacteria.Biometals. 2010; 23: 377-386Crossref PubMed Scopus (26) Google Scholar, 44Noinaj N. et al.Structural insight into the lactoferrin receptors from pathogenic Neisseria.J. Struct. Biol. 2013; 184: 83-92Crossref PubMed Scopus (26) Google Scholar]. 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Because many host nutritional immunity proteins also carry out crucial 'day jobs' in metal metabolism or transport, it is conceivable that antagonistic pleiotropy, or an evolutionary trade-off, could arise from an arms race with adverse consequences for the host. Sickle cell anemia in humans provides a quintessential example, whereby hemoglobin mutations confer resistance to malaria infection at the expense of severe anemia in homozygous carriers [59Ashley-Koch A. et al.Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review.Am. J. Epidemiol. 2000; 151: 839-845Crossref PubMed Scopus (348) Google Scholar]. Hereditary hemochromatosis (HH) is a condition characterized by increased iron absorption in the gut as well as serum iron overload, leading to iron accumulation in various organs and subsequent tissue damage [9Ganz T. Nemeth E. Hepcidin and disorders of iron metabolism.Annu. Rev. Med. 2011; 62: 347-360Crossref PubMed Scopus (372) Google Scholar, 60Vujić M. 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