Macrophages from C57BL/6J (B6) mice restrict growth of the intracellular bacterial pathogen Legionella pneumophila. Restriction of bacterial growth requires caspase-1 and the leucine-rich repeat-containing protein Naip5 (Birc1e) . We identified mutants of L. pneumophila that evade macrophage innate immunity. All mutants were deficient in expression of flagellin, the primary flagellar subunit, and failed to induce caspase-1-mediated macrophage death. Interestingly, a previously isolated flagellar mutant (fliI) that expresses, but does not assemble, flagellin did not replicate in macrophages, and induced macrophage death. Thus, flagellin itself, not flagella or motility, is required to initiate macrophage innate immunity. Immunity to Legionella did not require MyD88, an essential adaptor for toll-like receptor 5 (TLR5) signaling. Moreover, flagellin of Legionella and Salmonella induced cytotoxicity when delivered to the macrophage cytosol using Escherichia coli as a heterologous host. It thus appears that macrophages sense cytosolic flagellin via a TLR5-independent pathway that leads to rapid caspase-1-dependent cell death and provides defense against intracellular bacterial pathogens.
Legionella pneumophila is a bacterial pathogen that is the cause of a severe form of pneumonia known as Legionnaires' disease. A crucial aspect of the propensity of Legionella to cause disease lies in its ability to survive and multiply inside host immune cells known as macrophages. The intracellular survival and replication of Legionella can be studied using isolated macrophages grown in culture. Macrophages isolated from different laboratory mouse strains are differentially permissive for intracellular Legionella growth. This difference in permissiveness is genetic, and is conferred by differences in a mouse protein known as Naip5. The authors determined that Legionella strains that are unable to produce a protein called flagellin are able to grow inside normally resistant mouse macrophages. In addition, these flagellin − strains are defective in initiating a cell-death response on the part of infected macrophages. Based on these data, the authors suggest that there is an intracellular mechanism for detecting the presence of bacterial flagellin protein, and that a cell-death response is initiated upon the detection of flagellin.