1 Introduction

Zinc (Zn) is the second most abundant trace metal in living organisms and is involved in numerous aspects of life, including but not limited to DNA replication, transcription, protein synthesis, cell proliferation, apoptosis, and signal transduction. Both animals and microbes cannot naturally produce Zn, and the strategy for withholding and using Zn is vital to their survival and development [1, 2]. Within the expected concentration range, animals and microbes can regulate their internal Zn concentrations to maintain physiological metabolism [3, 4]. However, excess amounts of zinc ions (Zn2+) will lead to some cytotoxic effects, while zinc deficiency results in disruption of normal biological activities [3, 5].

Numerous studies have shown that zinc deficiency in animals leads to retarded growth, impaired immunity, and severe pathological changes in the body [4]. However, the host uses a similar strategy to reduce the zinc concentration in a single location against bacterial infection, which is called “nutritional immunity”, limiting the growth and virulence of pathogenic bacteria [6]. During the infectious process, some zinc-sequestering proteins, such as calprotectin, are expressed and recruited to the infection site to limit zinc acquisition by bacteria [7]. To survive in the host and succeed in competing with commensal microbes, pathogenic bacteria must maintain a steady state of zinc usage by controlling zinc distribution with zinc transporters [2, 3, 8]. The presence of zinc transporters in pathogenic bacteria also contributes to maintaining zinc homeostasis and virulence [2, 9]. Moreover, zinc acts as a direct or indirect regulator to affect the communication between nociceptor neurons and immune systems in the host, modulating the inflammatory response and host defence against bacterial infection [10,11,12].

Although nutritional immunity is termed a direct and effective antibacterial immune response, these mechanisms are not well described in the case of virus infection; for example, calprotectin did not to have a proven antiviral effect in published papers. However, zinc has been noted as a direct antiviral drug, as well as an antiviral immune stimulator and an indispensable component for the replication of many viruses [13,14,15]. Thus, zinc is likely to be a potential inter-kingdom signal between the host and microbes. In this review, we describe recent advances in understanding the role of zinc, similar to host hormones and quorum sensing (QS) of bacteria [16, 17], in modulating the communication between pathogenic microbes and their hosts.

2 Zinc homeostasis in bacteria

In addition to being a cofactor for some bacterial proteins, zinc ions are required for DNA repair, enzymatic reactions, responses to oxidative stress, and regulatory roles in other physiological processes in bacteria [2, 18]. Studies have shown that at least four kinds of zinc transport systems in bacteria, including two uptake transporters, ZnuACB and ZupT, and two export proteins, ZntA and ZitB, maintain zinc concentrations in the cell [2, 19]. As shown in Figure 1, under the pressure of a high Zn2+ concentration, the protein expression of P-type ATPase, cation diffusion facilitator (CDF) family of membrane transport, and resistance nodulation division (RND)-type efflux pumps are induced and protect bacteria from zinc poisoning [20, 21]. When zinc supplementation is sufficient for basic needs, bacteria synthesize low-affinity absorption systems to control zinc transport, such as the inorganic phosphate transport (Pit) system, which catalyses the rapid exchange of zinc via chemical osmotics [21]. Under zinc-limiting conditions, bacteria absorb and transport Zn2+ against zinc deficiency via a high-affinity ZnuACB uptake transporter [22, 23].

Figure 1
figure 1

Zinc transporter systems in bacteria [2, 9, 19,20,21,22]. Under zinc-replete conditions, membrane transport based on the P-type ATPase, CDF-type and RND-type families participates in zinc distribution. They work together to maintain zinc homeostasis in the cell. With sufficient zinc supplementation, bacteria control the cellular zinc concentration by a low-affinity absorption system, such as Pit and ZupT. Under zinc-limiting conditions, transporters of the high-affinity absorption system are induced and used to recruit Zn2+ against zinc deficiency, including ZnuACB, ZitB, ZnuD, etc.

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The ZnuACB transporter usually consists of three parts, including the periplasmic Zn2+-binding protein ZnuA, the inner membrane channel protein ZnuB and the ATP enzyme protein ZnuC, which is responsible for providing energy for Zn2+ transport [21]. ZinT and ZnuA have been shown to cooperate in periplasmic zinc recruitment, and the role of ZinT in the zinc uptake process is dependent on the presence of ZnuA [23, 24]. These genes are regulated by Zur, which not only blocks the binding of RNA polymerase and inhibits the expression of ZnuACB by Zn2Zur (or Zn4Zur) dimer protein but also regulates the mobilization of zinc through ribosomal proteins and leads to ZupT transporting Zn2+ rather than ZnuACB [18, 20]. Both ZupT and ZnuACB are necessary for bacteria to grow under zinc limitation; although ZnuACB usually obscures the role of ZupT, it also contributes to zinc uptake by Escherichia coli (E. coli) and Salmonella at a zinc concentration of 10 mM [25, 26].

In recent reports, the ZnuACB transport system is the most important zinc transport system in many bacteria [2, 27, 28]. znuA gene deletion can significantly reduce the adhesion of E. coli O157:H7 and Campylobacter jejuni to host cells [24, 29] and attenuate the pathogenicity of Brucella abortus, Salmonella enteritidis, and Pasteurella multocida to susceptible animals [27, 30]. The motility and biofilm formation of uropathogenic E. coli (UPEC) CFT073△znuB decreased compared with that of the wild-type strain [28]. After the znuACB gene was deleted, the virulence of Salmonella Typhimurium (STm) was weakened, but the existence of a ZnuACB transport system allowed the bacteria to resist calprotectin-mediated Zn2+ chelation and benefit from competition with host microflora [8, 27]. Our study also found that the ZnuACB system of enterotoxigenic E. coli (ETEC) F4ac plays an important role in maintaining the formation of biofilms and adherence to porcine small intestinal epithelial cells in vitro under zinc deficiency [78, 108, 123, 133]. The dynamic change in competition in zinc acquisition between the host and pathogens is complicated. In addition to playing a role in enzymes and structural cofactors for the survival of all organisms, zinc also affects the activity of some transmembrane receptor proteins, including TLRs, which are responsible for the recognition of microbes or antigen molecules and the development and modulation of immune responses. Upon pathogen attack, some zinc-sequestering proteins are expressed and recruited to the infected site to chelate zinc ions and limit the growth and virulence of pathogenic bacteria, such as calprotectin, also known as the S100A8/S100A9 heterodimer, which is vital for strategic nutritional immunity. During the infectious process, the host also releases other S100 proteins, and then the binding of S100 proteins to cell surface receptors, such as TLR4, RAGE, and GPCRs, plays an important role in the regulation of inflammatory signal transduction. In turn, by regulating downstream signalling pathways, zinc can enhance the integrity of the intestinal mucosal barrier and reduce inflammation and diarrhoea caused by pathogenic infection.

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