Natural Competence Promotes Helicobacter pylori Chronic Infection.

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Abstract:

Animal models are important tools for studies of human disease, but developing these models is a particular challenge for organisms with restricted host ranges, such as the human stomach pathogen Helicobacter pylori. In most cases, H. pylori infects the stomach for many decades before symptoms appear, distinguishing it from many bacterial pathogens that cause acute infection. To model chronic infection in the mouse, a human clinical isolate was selected for its ability to survive for two months in the mouse stomach and the resulting strain, MSD132, colonized the mouse stomach for at least 28 weeks. During selection, the cagY component of the Cag type-IV secretion system was mutated, disrupting a key interaction with host cells. Increases in both bacterial persistence and bacterial burden occurred prior to this mutation and a mixed population of cagY+ and cagY- cells was isolated from a single mouse, suggesting that mutations accumulate during selection and that factors in addition to the Cag apparatus are important for murine adaptation. Diversity in both alleles and genes is common in H. pylori strains and natural competence mediates a high rate of inter-strain genetic exchange. Mutants of the Com apparatus, a membrane DNA transporter, and DprA, a cytosolic competence factor, showed reduced persistence, although initial colonization was normal. Thus, exchange of DNA between genetically heterogeneous H. pylori may improve chronic colonization. The strains and methods described here will be important tools for defining both the spectrum of mutations that promote murine adaptation and the genetic program of chronic infection.