Characterization in Helicobacter pylori of a Nickel Transporter Essential for Colonization That Was Acquired during Evolution by Gastric Helicobacter Species

Abstract

Metal acquisition is crucial for all cells and for the virulence of many bacterial pathogens. In particular, nickel is a virulence determinant for the human gastric pathogen Helicobacter pylori as it is the cofactor of two enzymes essential for in vivo colonization, urease and a [NiFe] hydrogenase. To import nickel despite its scarcity in the human body, H. pylori requires efficient uptake mechanisms that are only partially defined. Indeed, alternative ways of nickel entry were predicted to exist in addition to the well-described NixA permease. Using a genetic screen, we identified an ABC transporter, that we designated NiuBDE, as a novel H. pylori nickel transport system. Unmarked mutants carrying deletions of nixA, niuD and/or niuB, were constructed and used to measure (i) tolerance to toxic nickel exposure, (ii) intracellular nickel content by ICP-OES, (iii) transport of radioactive nickel and (iv) expression of a reporter gene controlled by nickel concentration. We demonstrated that NiuBDE and NixA function separately and are the sole nickel transporters in H. pylori. NiuBDE, but not NixA, also transports cobalt and bismuth, a metal currently used in H. pylori eradication therapy. Both NiuBDE and NixA participate in nickel-dependent urease activation at pH 5 and survival under acidic conditions mimicking those encountered in the stomach. However, only NiuBDE is able to carry out this activity at neutral pH and is essential for colonization of the mouse stomach. Phylogenomic analyses indicated that both nixA and niuBDE genes have been acquired via horizontal gene transfer by the last common ancestor of the gastric Helicobacter species. Our work highlights the importance of this evolutionary event for the emergence of Helicobacter gastric species that are adapted to the hostile environment of the stomach where the capacity of Helicobacter to import nickel and thereby activate urease needs to be optimized.

Genomics of Helicobacter pylori

“…Nickel is a cofactor of urease (essential for surviving the acidic environment of the stomach) and thus is a virulence determinant for gastric colonization. The gene niuBDE , identified by Fisher et al., for the first time, is responsible not only for the transport of nickel, but also for the transport of cobalt and bismuth, a metal often used for H. pylori therapy …”

Selective substrate uptake: The role of ATP-binding cassette (ABC) importers in pathogenesis

“…Nickel import is controlled by several uptake systems, including a member of the Peptide, Opine and Nickel Uptake (PepT) transporter family, CntABCDF, and a recently discovered nickel transporter, NiuBDE. Recent work has identified gastric Helicobacter species that have acquired nickel transporter genes through horizontal gene transfer [53]. Whereas NiuBDE and NixA function independently to transport nickel, both transporters participate in nickel-dependent urease activation at pH 5 and promote survival of H. pylori in the acidic environment of the stomach.…”

“…Whereas NiuBDE and NixA function independently to transport nickel, both transporters participate in nickel-dependent urease activation at pH 5 and promote survival of H. pylori in the acidic environment of the stomach. However, only NiuBDE transports transport nickel for urease activation at neutral pH and is essential for colonization of the mouse stomach suggesting preferential transport of nickel with changing microenvironments [53]. S. aureus cntABCDF , originally annotated as opp1 , is a cobalt and nickel transporter that impacts urease activity and bacterial colonization in the systemic and urinary tract infection models.…”

The Human Nickel Microbiome and its relationship to Allergy and Overweight in Women

“…It is important to note that 50mM is fraction of the Nickel solution that is commonly used for metallurgic electroplating and never in humans it has been reported bacteria able to tolerate NiSO4 concentration of this magnitude, not even Helicobacter Pylori [32].…”