Flagellin is Critical for Legionella Motility and Macrophage Recognition.

The causative agent of Legionnaires’ disease is L. pneumophila, an intracellular pathogen that infects aquatic amoebae and alveolar macrophages. L. pneumophila expresses virulence factors that are important for growth in mammalian macrophages and transmission from one host cell to the next, specifically motility, stress resistance and cytotoxicity to macrophages. A correlative study of nosocomial Legionnaires’’ disease and colonization of the corresponding hospital water systems provided the opportunity to determine how well widely used laboratory assays correlate with the virulence potential of Legionella isolates. I found that disease incidence of the L. pneumophila isolates correlated with one laboratory test of virulence, the ability to survive in the stringent environment of primary mouse macrophages; nevertheless, motility and cytotoxicity were conserved across all strains. The flagellum is essential for motility and dispersal of Legionella in aquatic environments. Furthermore, mouse resistance to L. pneumophila is accomplished through macrophage recognition of the major flagellar protein, flagellin. Macrophage innate defenses are triggered by cytosolic flagellin, independently of TLR5, by a pathway that includes the NOD-like cytosolic protein Naip5, requires caspase-1, and that effectively restricts replication of L. pneumophila within cultured macrophages and mouse lungs. To elucidate the factors that contribute to restriction in C57Bl/6 macrophages, I analyzed the ability of flagellate Legionella species that replicate to trigger a pro-inflammatory innate response. In summary, I provide evidence that L. pneumophila is a potent trigger of the innate immune system of macrophages as a result of cytosolic contamination that requires two key bacterial factors: pore formation and flagellin. Studying non-pneumophila species of Legionella has extended the evidence that translocation by the type IV secretion system is critical to recognition of flagellin.PhDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/62336/1/nwhitfie_1.pd