Nutritional immunity with metals By Dr. Kevin Waldron, Newcastle University, UK


The spread of antibiotic resistance among disease-causing (pathogenic) bacteria is causing increasing consternation among medical and veterinary professionals, researchers, and policymakers worldwide. As a result, there is regulatory pressure to significantly reduce antibiotic usage, both in human medicine and in agriculture, in an effort to control the worrying spread of antibiotic resistance among bacteria. Simultaneously, both academic and industrial researchers are being encouraged to find new, innovative ways to treat future infections. In order to produce such novel antibiotics of the future, much current research is aimed at better understanding how pathogenic bacteria are naturally controlled by the mammalian immune system, in the hope that novel therapeutic strategies can be designed that mimic or exploit these processes. To successfully establish an infection, once inside the host


organism an invading pathogenic microbe must obtain all of its nutritional requirements directly from the host. This creates an opportunity for the immune system to try to limit the pathogen’s growth by making it difficult for the microbe to acquire a sufficient supply of essential nutrients. This immune strategy is called ‘nutritional immunity’. An effective use of this strategy by the immune system involves


enforcing strict control of the availability of trace minerals during infection. The same metal ions (iron, zinc and manganese, for example) are essential micronutrients for both bacteria and mammals, in which they are exploited as critical cofactors that enable enzymes to catalyse chemical reactions. This creates a competition for these metals at the host-pathogen interface. Their essential nature has led to the evolution of complex metal homeostasis systems in all cells that precisely coordinate metal acquisition, delivery to metal-requiring proteins, and detoxification of excess metal concentrations through storage or export.


The iron-withholding response The concept of ‘nutritional immunity’ is not new. It has been long established that the mammalian immune response to a bacterial infection alters host iron homeostasis in ways that restrict the ability of the invading bacteria to acquire this trace mineral. When an infection is detected by the immune system, a series of signal cascades result in: (i) decreased iron uptake from the intestine into the bloodstream; (ii) increased expression of the iron-transporting protein transferrin in the blood, which coordinates the circulating iron so tightly that most bacteria struggle to compete; (iii) increased storage of iron within host cells to make it more difficult for bacteria in the blood to access this precious resource; and (iv) production of immune proteins that function to interfere with bacterial iron acquisition systems. This global iron response is mediated by the hormone hepcidin, whose synthesis in the liver is influenced by immune signalling (Figure 1).


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Figure 1: The iron-withholding response of the mammalian immune system. Schematic diagram illustrating how, in response to infection and inflammation, bodily iron homeostasis is altered to make this essential trace mineral less bioavailable to the invading microbe. Intestinal iron absorption is decreased, iron storage in tissues is increased, and circulating iron in the blood is protected by induction of the iron-sequestering protein transferrin. These changes are regulated systemically by the hormone, hepcidin.


The central role of calprotectin in nutritional immunity This long-established concept has, however, been greatly extended over the last decade to incorporate immune responses that regulate the availability of other essential metal ions in response to bacterial infection. The central player in this wider metal-depriving response is calprotectin, a protein complex that is produced and secreted in very large quantities, primarily by a specific type of immune cells called neutrophils, once activated through detection of bacterial pathogens. Calprotectin exhibits extremely tight binding affinities for a range of metals, including manganese, zinc and iron, all of which are essential in biology, and there is accumulating evidence that calprotectin can influence the competition for each of these metal ions at the host- pathogen interface. The role of calprotectin in nutritional immunity was first


discovered through study of its role in skin and soft tissue infections caused by the Gram positive bacterium, Staphylococcus aureus. This organism has gained infamy through the spread of strains that


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