The CpxRA Two-Component System Is Essential for Citrobacter rodentium Virulence

<jats:title>ABSTRACT</jats:title> <jats:p> <jats:named-content content-type="genus-species">Citrobacter rodentium</jats:named-content> is a murine intestinal pathogen used as a model for the foodborne human pathogens enterohemorrhagic <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> and enteropathogenic <jats:named-content content-type="genus-species">E. coli</jats:named-content> . During infection, these pathogens use two-component signal transduction systems to detect and adapt to changing environmental conditions. In <jats:named-content content-type="genus-species">E. coli</jats:named-content> , the CpxRA two-component signal transduction system responds to envelope stress by modulating the expression of a myriad of genes. Quantitative real-time PCR showed that <jats:italic>cpxRA</jats:italic> was expressed in the colon of C57BL/6J mice infected with <jats:named-content content-type="genus-species">C. rodentium</jats:named-content> . To determine whether CpxRA plays a role during <jats:named-content content-type="genus-species">C. rodentium</jats:named-content> infection, a <jats:italic>cpxRA</jats:italic> deletion strain was generated and found to have a colonization defect during infection. This defect was independent of an altered growth rate or a defective type III secretion system, and single-copy chromosomal complementation of <jats:italic>cpxRA</jats:italic> restored virulence. The <jats:named-content content-type="genus-species">C. rodentium</jats:named-content> strains were then tested in C3H/HeJ mice, a lethal intestinal infection model. Mice infected with the Δ <jats:italic>cpxRA</jats:italic> strain survived infection, whereas mice infected with the wild-type or complemented strains succumbed to infection. Furthermore, we found that the <jats:italic>cpxRA</jats:italic> expression level was higher during early infection than at a later time point. Taken together, these data demonstrate that the CpxRA two-component signal transduction system is essential for the <jats:italic>in vivo</jats:italic> virulence of <jats:named-content content-type="genus-species">C. rodentium</jats:named-content> . In addition, these data suggest that fine-tuned <jats:italic>cpxRA</jats:italic> expression is important for infection. This is the first study that identifies a <jats:named-content content-type="genus-species">C. rodentium</jats:named-content> two-component transduction system required for pathogenesis. This study further indicates that CpxRA is an interesting target for therapeutics against enteric pathogens. </jats:p>