Co‐ordinate expression of virulence genes during swarm‐cell differentiation and population migration of Proteus mirabilis

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Abstract
The uropathogenic Gram-negative bacterium Proteus mirabilis exhibits a form of multicellular behaviour termed swarming, which involves cyclical differentiation of typical vegetative cells into filamentous, multi-nucleate, hyperflagellate swarm cells capable of rapid and co-ordinated population migration across surfaces. We observed that differentiation into swarm cells was accompanied by substantial increases in the activities of intracellular urease and extracellular haemolysjn and metalloprotease, which are believed to be central to the pathogenicity of P. mirabills. In addition, the ability of P. mirabilis to invade human urothelial cells in vitro was primarily a characteristic of differentiated swarm cells, not vegetative cells. These virulence factor activities fell back as the cells underwent cyclical reversion to the vegetative form (consolidation), in parallel with the diagnostic modulation of flagellin levels on the cell surface. Control cellular alkaline phosphatase activities did not increase during differentiation or consolidation. Non-flagellated, non-motile transposon insertion mutants were unable to invade urothelial cells and they generated only low-level activities of haemolysin, urease and protease (0–10% of wild type). Motile mutants unable to differentiate into swarm cells were comparably reduced in their haemolytic, ureolytic and invasive phenotypes and generated threefold less protease activity. Mutants that were able to form swarm cells but exhibited various aberrant patterns of swarming migration produced wild-type activities of haemotysin, urease and protease, but their ability to enter urothelial cells was three- to 10-fold lower. Analysis of haemolysin (hpmA) transcripts showed that during swarm cell differentiation there was a c. 50-fold increase in the level of the predicted major 5.2 kb and minor 6.9 kb mRNAs transcribed from the hpm operon, and assay of mRNA complimentary to urease (ureC) and flagellin (fliC) gene sequences confirmed that modulation of virulence factor activity during the swarming cycle resulted from differential expression of virulence genes in parallel with fliC gene expression. Hybridization of stage-specific mRNA with 30 random, non-overlapping chromosomal gene probes provided no evidence for universal changes in the expression of the P. mirabiis genome, suggesting that differential virulence gene expression may be a specific strategy.