Comparative genomics and proteomics of Helicobacter mustelae, an ulcerogenic and carcinogenic gastric pathogen

Abstract

BackgroundHelicobacter mustelae causes gastritis, ulcers and gastric cancer in ferrets and other mustelids. H. mustelae remains the only helicobacter other than H. pylori that causes gastric ulceration and cancer in its natural host. To improve understanding of H. mustelae pathogenesis, and the ulcerogenic and carcinogenic potential of helicobacters in general, we sequenced the H. mustelae genome, and identified 425 expressed proteins in the envelope and cytosolic proteome.ResultsThe H. mustelae genome lacks orthologs of major H. pylori virulence factors including CagA, VacA, BabA, SabA and OipA. However, it encodes ten autotransporter surface proteins, seven of which were detected in the expressed proteome, and which, except for the Hsr protein, are of unknown function. There are 26 putative outer membrane proteins in H. mustelae, some of which are most similar to the Hof proteins of H. pylori. Although homologs of putative virulence determinants of H. pylori (NapA, plasminogen adhesin, collagenase) and Campylobacter jejuni (CiaB, Peb4a) are present in the H. mustelae genome, it also includes a distinct complement of virulence-related genes including a haemagglutinin/haemolysin protein, and a glycosyl transferase for producing blood group A/B on its lipopolysaccharide. The most highly expressed 264 proteins in the cytosolic proteome included many corresponding proteins from H. pylori, but the rank profile in H. mustelae was distinctive. Of 27 genes shown to be essential for H. pylori colonization of the gerbil, all but three had orthologs in H. mustelae, identifying a shared set of core proteins for gastric persistence.ConclusionsThe determination of the genome sequence and expressed proteome of the ulcerogenic species H mustelae provides a comparative model for H. pylori to investigate bacterial gastric carcinogenesis in mammals, and to suggest ways whereby cag minus H. pylori strains might cause ulceration and cancer.The genome sequence was deposited in EMBL/GenBank/DDBJ under accession number FN555004.

An ABC Transporter and a TonB Ortholog Contribute to Helicobacter mustelae Nickel and Cobalt Acquisition

“…1B). Interestingly, the genome sequences of H. pylori and H. mustelae lack genes encoding clear candidates for heme transporters (22,35), and although our studies did not allow us to identify a heme transporter, we were able to demonstrate that a tonB1 mutant was unable to grow on heme as the sole iron source (Fig. 1B), suggesting a role for a TonB-dependent outer membrane receptor.…”

“…A comparison of the complete genome sequences of Helicobacter species previously suggested that only the H. hepaticus genome contains a complete ABC transporter system for nickel (4), while the H. pylori, H. acinonychis, and H. mustelae genome sequences lack a clear candidate for such an ABC transporter (12,22,35), with only the predicted ferric citrate permease and ATPase FecDE and a CeuE periplasmic binding protein for enterochelin being annotated (12,22,35). Our findings that FecD and CeuE are involved in nickel acquisition are in agreement with the absence of Fur-and iron-responsive regulation of these genes in H. pylori (39) and H. mustelae (Fig.…”

“…This redresses the apparent imbalance between iron and nickel acquisition genes in the H. mustelae genome sequence (4,22,48), since several genes previously annotated as being involved in iron acquisition can now be reclassified.…”

“…HELICOBACTER MUSTELAE NICKEL AND COBALT ACQUISITION 4265 1A), the location of the H. mustelae ceuE gene directly downstream of the nikH gene (22,34), the nickel-responsive regulation of ceuE in H. pylori (7), and the predicted NikR operators in the H. pylori fecDE promoter (34). Data from the mutational studies also suggest that H. mustelae contains two separate acquisition pathways for nickel, based on the TonB2-energized NikH outer membrane transporter and the NixA inner membrane transporter, whereas the CeuE/FecDE ABC transporter functions independently (Fig.…”

“…The urease enzyme is the main factor allowing acid resistance, whereas hydrogenase is important for energy production, and both enzymes are essential for gastric colonization by Helicobacter species (2,20,32,37). Analyses of complete genome sequences of gastric Helicobacter species allowed the prediction of many genes putatively involved in iron acquisition but surprisingly few predicted nickel acquisition genes (12,22,35).…”