A Positively Selected fur -R88H Mutation Enhances Helicobacter pylori Fitness in a High-Salt Environment and Alters Fur-Dependent Regulation of Gene Expression

Both Helicobacter pylori infection and a high-salt diet are risk factors for gastric cancer. We previously showed that a mutation in (encoding the ferric uptake regulator variant Fur-R88H) was positively selected in H. pylori strains isolated from experimentally infected Mongolian gerbils receiving...

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Bibliographic Details
Published in:Infection and immunity 2023-02, Vol.91 (2), p.e0042022-e0042022
Main Authors: Loh, John T, Struttmann, Emily L, Favret, Natalie, Harvey, M Lorena, Pakala, Suman B, Chopra, Abha, McClain, Mark S, Cover, Timothy L
Format: Article
Language:English
Subjects:
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Gene Expression Regulation, Bacterial
Helicobacter Infections
Helicobacter pylori - genetics
Helicobacter pylori - physiology
Humans
Microbial Pathogenesis
Molecular Pathogenesis
Mutation
Repressor Proteins - genetics
Repressor Proteins - metabolism
Sodium Chloride - metabolism
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Summary:Both Helicobacter pylori infection and a high-salt diet are risk factors for gastric cancer. We previously showed that a mutation in (encoding the ferric uptake regulator variant Fur-R88H) was positively selected in H. pylori strains isolated from experimentally infected Mongolian gerbils receiving a high-salt diet. In the present study, we report that continuous H. pylori growth in high-salt conditions also leads to positive selection of the -R88H mutation. Competition experiments with strains containing wild-type or -R88H, each labeled with unique nucleotide barcodes, showed that the -R88H mutation enhances H. pylori fitness under high-salt conditions but reduces H. pylori fitness under routine culture conditions. The fitness advantage of the -R88H mutant under high-salt conditions was abrogated by the addition of supplemental iron. To test the hypothesis that the -R88H mutation alters the regulatory properties of Fur, we compared the transcriptional profiles of strains containing wild-type or -R88H. Increased transcript levels of , which encodes a predicted TonB-dependent outer membrane transporter, were detected in the -R88H variant compared to those in the strain containing wild-type under both high-salt and routine conditions. Competition experiments showed that contributes to H. pylori fitness under both high-salt and routine conditions. These results provide new insights into mechanisms by which the -R88H mutation confers a selective advantage to H. pylori in high-salt environments.
ISSN:0019-9567
1098-5522
DOI:10.1128/iai.00420-22