Common themes and unique proteins for the uptake and trafficking of nickel, a metal essential for the virulence of Helicobacter pylori

Abstract

Nickel is a virulence determinant for the human gastric pathogen Helicobacter pylori. Indeed, H. pylori possesses two nickel-enzymes that are essential for in vivo colonization, [NiFe] hydrogenase and urease, an abundant virulence factor that contains 24 nickel ions per active complex. Because of these two enzymes, survival of H. pylori relies on an important supply of nickel, implying a tight control of its distribution and storage. In this review, we will present the pathways of activation of the nickel enzymes as well as original mechanisms found in H. pylori for the uptake, trafficking and distribution of nickel between the two enzymes. These include (i) an outer-membrane nickel uptake system, the FrpB4 TonB-dependent transporter, (ii) overlapping protein complexes and interaction networks involved in nickel trafficking and distribution between urease and hydrogenase and, (iii) Helicobacter specific nickel-binding proteins that are involved in nickel storage and can play the role of metallo-chaperones. Finally, we will discuss the implication of the nickel trafficking partners in virulence and propose them as novel therapeutic targets for treatments against H. pylori infection.

Nickel Sequestration by the Host-Defense Protein Human Calprotectin

“…12 CP is capable of inhibiting the growth of S. aureus (Figure S10A), and this organism utilizes urease during infection. 14,15 On the basis of the Ni(II)-uptake study (Figure 4), we hypothesized that Ni(II) sequestration by CP in the extracellular space would perturb intracellular Ni(II) homeostasis and diminish the urease activity of S. aureus .…”

“…68,69 Given that CP is present in these physiological locales where urea is abundant and where microbial pathogens are known to colonize, our work affords a new hypothesis that human CP may be involved in the homeostasis of Ni(II) at the host- microbe interface. In addition to human pathogens such as S. aureus and K. pneumoniae , the role of Ni(II) is established for the virulence of H. pylori , 14,70 and whether CP influences Ni(II) trafficking and utilization in H. pylori and other gastrointestinal pathogens during infection is an avenue for future research.…”

“…8 In the context of infectious disease, recent reports have highlighted the importance of Ni(II) import systems for the growth and virulence of the pathogenic bacterium Staphylococcus aureus under metal-depleted conditions in vitro and in animal models of infection. 9-11 Furthermore, urease is an enzyme that contributes to the virulence of human pathogens, 12,13 including Helicobacter pylori , 14 Staphylococcus spp., 15,16 and Klebsiella pneumoniae . 17 In contrast, less is known about nickel homeostasis in mammals and other higher organisms, and no mammalian nickel-dependent enzyme has been identified.…”

Metal economy in host-microbe interactions

“…Guilhen et al (2013) focus on families of exporters and the role of metal efflux in the evolution of Neisseria meningitidis virulence and naso-pharyngeal colonization. De Reuse et al (2013) present the specific nickel needs of the gastric pathogen Helicobacter pylori and the homeostasis of nickel in this bacterium. Finally, Zn homeostasis is the subject of two articles.…”

"Synthesis, Spectroscopic, and Biological Activity Studies of the Ni(ii) Complexes of Tridentate Schiff Bases "

“…These nickel trafficking enzymes contribute to virulence and are probable therapeutic targets for dealing with H. pylori infections. 10,11 Nickel is found in RNA and imagined to be involved in protein function. Nickel is thought to be involved in the breakdown of glucose and in prolactin production.…”