Legionella pneumophila thrives in aquatic environments within protozoa and biofilms. As a consequence of its co-evolution with amoebae, L. pneumophila has acquired traits that also promote opportunistic infection of human alveolar macrophages. To survive and proliferate, the bacterium differentiates into replicative or transmissive cell types. When conditions deteriorate, bacteria transform into a motile, resilient form equipped to disperse in the environment and invade a new host cell. In favorable conditions, L. pneumophila represses transmission factors and activates those for replication. To coordinate timely differentiation, L. pneumophila controls its pool of guanosine tetraphosphate (ppGpp). Two enzymes are dedicated to ppGpp metabolism: RelA, and SpoT. In broth culture, RelA responds to amino acid starvation and SpoT to perturbations in fatty acid biosynthesis, likely by interacting with acyl carrier protein. As both a synthetase and hydrolase of ppGpp, SpoT is essential for L. pneumophila both to initiate replication and survive transmission between macrophages. To mediate the response to ppGpp, L. pneumophila employs the transcription factor DksA. In broth culture, ppGpp and DksA cooperate to activate transmission traits. However, during transit between macrophages, ppGpp is essential, whereas DksA is dispensable; therefore, ppGpp can also act autonomously. To study the functional relationship between ppGpp and DksA, the L. pneumophila flagellar biosynthetic gene cascade was exploited. The bacterial flagellum is assembled from ~ 20,000 filament subunits. In L. pneumophila, the FliA sigma factor activates transcription of flaA, encoding the major filament protein. During replication, DksA maintains basal fliA transcription. When deteriorating conditions demand rapid dispersal, bacteria synthesize ppGpp, which cooperates with DksA to amplify fliA and flaA expression. In part, activation is achieved by transcriptional initiation of two non-coding RNAs, RsmY and RsmZ, which negatively regulate a global repressor, CsrA. By controlling expression of RsmY/Z, ppGpp also derepresses an activator of fliA transcription to promote final assembly of the flagellum. Many bacteria rely on alarmones to cue disturbances and coordinate survival and virulence programs. Its strict reliance on ppGpp for transmission makes L. pneumophila an attractive experimental model to understand how metabolic cues are transmitted by second messenger signaling pathways to govern bacterial virulence
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