Significance of zinc in innate immune defense against Streptococcus pyogenes.

When we think about trace elements and bacterial virulence, iron is usually the first metal that comes up. Zinc, although often forgotten, is the second most abundant trace element, after iron, in humans. Plasma concentrations of zinc range between 12 and 16 μM, and practically all zinc is bound to albumin or other proteins [1]. Zinc is found at low levels on mucosal surfaces; in sputum and bronchoalveolar lavage the zinc concentration is about 1 μM. Zinc deficiency is associated with susceptibility to infectious diseases, such as otitis media or those causing diarrhea. Several studies suggest that zinc supplementation may lower the risk of these infections [1–3]. This supplementation is especially relevant in undernourished children. Zinc is thought to be important in the control of immune reactions and defense against bacteria. In humans, zinc levels increase during inflammation and infection in some body compartments, whereas plasma levels actually may decrease [1]. This shift is presumably caused by redistribution of plasma zinc to the liver, where zinc transporters are upregulated. The liver also produces zincbinding metallothioneins, which are intracellular proteins functioning in metal storage and transport. The neutrophil protein calprotectin is capable of binding zinc and manganese. Calprotectin released from activated neutrophils affects the free levels of these trace elements at the site of the infection [4]. The chelation of zinc and manganese by calprotectin has also been shown to inhibit staphylococcal growth in tissue abscesses in a mouse model [5, 6]. This inhibitory effect has not yet been shown in other bacteria. Zinc is also essential for bacterial life. Zinc is associated with about 5% of bacterial proteins, and several important enzymes require zinc for activity [3]. Zinc is involved in the control of gene expression and cellular metabolism. Since the host immune system is capable of sequestering zinc, which results in zinc deprivation, human pathogens have developed mechanisms to maintain adequate intracellular zinc levels. One of these mechanisms is the expression of high-affinity zinc transporters in response to decreased zinc levels in the environment [3].Most of these transporters belong to the ZnuABC transport system family, originally described in Escherichia coli. Inactivation of these transporters has been shown to decrease the virulence capacity of several bacterial pathogens, such as Salmonella enterica, E. coli, and Streptococcus pyogenes [3]. Even though zinc is necessary for bacterial survival, increased amounts of zinc can be detrimental for the pathogen [7]. Therefore, it is essential for bacteria to maintain tight zinc homeostasis. In addition to zinc transporters, cells may express zinc exporters, which pump zinc out of the cell [1, 8]. In streptococci, these efflux pumps provide resistance against at least zinc and cobalt. Ong et al [8], in this issue of the Journal, have studied the role of zinc in the innate immune defense against S. pyogenes (group A streptococcus [GAS]). GAS is an important pathogen associated with significant morbidity and mortality, both in developed and developing countries. The innate immune defense against GAS relies mainly on neutrophils as the first-line responders. GAS, as well as other streptococci, is known to possess several genes involved in zinc homeostasis. Zinc-dependent repressor AdcR regulates genes in control of zinc acquisition. It is known that GAS has a czcD gene, which encodes a cation-diffusion facilitator [1, 8]. In addition, the gene pmtA is suspected to be associated with zinc efflux in GAS [9]. The study by Ong et al shows that zinc homeostasis is crucial for GAS virulence. Received 14 January 2014; accepted 17 January 2014; electronically published 20 January 2014. Correspondence: Hanna Jarva, MD, PhD, Haartman Institute, Department of Bacteriology and Immunology, PO Box 21, 00014 University of Helsinki, Finland (hanna.jarva@ helsinki.fi). The Journal of Infectious Diseases 2014;209:1495–6 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu055