Evidence of a role for the F1 capsule of in enhancing transmission from mammals to fleas in a mouse model of bubonic plague.

The F1 protein capsule of is encoded by the operon on the 100 kb plasmid pFra and is produced at high levels in the mammalian host. Although the F1 capsule is not an essential virulence factor in many mammals, isolates lacking the operon are very rare in nature, indicating an essential biological role. Here, we show that F1-negative Δ mutants of are virulent in a mouse model but with a longer time to terminal disease. Bacterial loads in the spleen at the terminal stage of plague were not significantly different from the wild type. However, the level of bacteremia reached by the Δ mutants was often significantly lower than the wild type. Fleas that fed on moribund mice infected with the Δ mutants ingested the expected number of bacteria, but most mice had levels of bacteremia too low to support the development of a transmissible infection in the flea. A complemented Δ mutant restored wildtype levels of bacteremia and median time to death. F1-negative have a more pronounced autoaggregative phenotype, both and , which likely leads to a higher degree of sequestration in the spleen and other tissues. Therefore, an important biological role of the F1 capsule may be to enable to achieve bacteremia levels high enough to efficiently infect fleas, thereby enhancing stable flea-borne transmission cycles of .IMPORTANCEArthropod-borne pathogens face two fundamental challenges in completing their life cycle-they must produce a transmissible infection in both their mammalian and arthropod hosts. In order to effectively infect its flea vector, , the bacterial agent of plague, must generate a high-density bacteremia in the mammalian hosts that the fleas feed upon. In this study, we found that the F1 protein capsule of enhances the production of high bacteremia at the terminal stage of plague in a mouse model, thereby promoting successful mammal-to-flea transmission. Acquisition of the plasmid that encodes the F1 capsule occurred early in the evolutionary divergence of from and was likely to have been a key step in the transition to a flea-borne lifestyle.