Nickel Homeostasis in Helicobacter Species

Gastric Helicobacter species are adapted to colonize the acidic environment of the stomach. Colonization with H pylori is life long if untreated, and can lead to gastritis, peptic ulcer disease and eventually to gastric cancer. Although H pylori is sensitive to many antibiotics in vitro, only a limited number of antibiotics can be used in vivo while increasing resistance against these therapeutics significantly impairs the treatment of H pylori infection. Metals play an essential role in the metabolism of all living organisms, including gastric Helicobacter species, but can also be deleterious when metal availability is either too low or too high. Therefore cells need to maintain homeostasis of intracellular metal concentrations to allow survival and growth. A better understanding of metal homeostasis in gastric Helicobacter species may allow for the knowledge-led development of therapeutics which are based on disturbing the balance of the intracellular metal concentrations to either toxicity or restriction. The focus of this PhD-thesis is on nickel metabolism, since this metal is the cofactor of the urease enzyme and hydrogenase enzyme, both essential for colonization of gastric Helicobacter species. The high expression level of the urease enzyme mediates acid resistance in the presence of urea, but also necessitates the import of relatively high concentrations of nickel. Although transcriptional regulation by the nickel-dependent regulator NikR has been studied, relative little is known about which proteins are involved in actual transport of nickel. The genome era has opened the possibility of functional genomics investigations, using the information from the genomes of different Helicobacter species. Many of the genes of Helicobacter species do not yet have a predicted function, or have been assigned a putative function only based on homology with genes from other bacterial species. Comparison of the genomic content of different Helicobacter species and transcriptional and functional characterization of the genes putatively involved in nickel homeostasis, as presented in this thesis, will provide more insight in how these bacteria are able to acquire sufficient concentrations of nickel.

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