Intra-Species and Inter-Kingdom Signaling of Legionella pneumophila

Abstract

The ubiquitous Gram-negative bacterium Legionella pneumophila parasitizes environ mental amoebae and, upon inhalation, replicates in alveolar macrophages, thus causing a life-threatening pneumonia called "Legionnaires' disease." The opportunistic pathogen employs a bi-phasic life cycle, alternating between a replicative, non-virulent phase and a stationary, transmissive/virulent phase. L. pneumophila employs the Lqs (Legionella quorum sensing) system as a major regulator of the growth phase switch. The Lqs system comprises the autoinducer synthase LqsA, the homologous sensor kinases LqsS and LqsT, as well as a prototypic response regulator termed LqsR. These components produce, detect, and respond to the α-hydroxyketone signaling molecule LAI-1 (Legionella autoinducer-1, 3-hydroxypentadecane-4-one). LAI-1-mediated signal transduction through the sensor kinases converges on LqsR, which dimerizes upon phosphorylation. The Lqs system regulates the bacterial growth phase switch, pathogen-host cell interactions, motility, natural competence, filament production, and expression of a chromosomal "fitness island." Yet, LAI-1 not only mediates bacterial intra-species signaling, but also modulates the motility of eukaryotic cells through the small GTPase Cdc42 and thus promotes inter-kingdom signaling. Taken together, the low molecular weight compound LAI-1 produced by L. pneumophila and sensed by the bacteria as well as by eukaryotic cells plays a major role in pathogen-host cell interactions.

Keywords: Dictyostelium; Legionella; amoeba; autoinducer; bacterial pathogenesis; cell–cell communication; macrophage; phospho-transfer; quorum sensing; response regulator; sensor kinase; small molecule signaling; α-hydroxyketone.

FIGURE 1

LAI-1-mediated intra-species and inter-kingdom signaling of Legionella pneumophila. The amoebae-resistant opportunistic pathogen L. pneumophila colonizes different niches in the environment, including biofilms and protozoa. L. pneumophila employs a bi-phasic life cycle, alternating between a replicative and a stationary/transmissive phase. As a major regulator of the growth phase switch L. pneumophila employs the Lqs system, which produces, detects, and responds to the AHK (α-hydroxyketone) signaling molecule LAI-1 (Legionella autoinducer-1; 3-hydroxypentadecane-4-one). The Lqs system comprises the autoinducer synthase LqsA, the sensor kinases LqsS and LqsT, as well as the response regulator LqsR. The system regulates the bacterial growth phase switch, virulence, motility, filaments, and competence. LAI-1 not only promotes bacterial cell–cell communication and quorum sensing, but also modulates the migration of eukaryotic cells through a pathway requiring the scaffold protein IQGAP1, the small GTPase Cdc42 and its activator ARHGEF9. The eukaryotic LAI-1 receptor(s) is/are unknown [?]. Solid and dashed lines represent known/direct or hypothetical/indirect pathways, respectively.

FIGURE 2

Two-component systems (TCSs) controlling the bi-phasic life cycle of L. pneumophila. The TCSs LqsRS, LetAS, PmrAB, and CpxRA, as well as the RsmYZ-CsrA regulatory unit are illustrated. Under conditions of nutrient abundance the RNA-binding carbon storage regulator A (CsrA) represses transmission traits and promotes replication. Upon nutrient depletion (at the onset of stationary phase), LetAS and the sigma factor RpoS up-regulate transmission traits. LetA induces the small non-coding snRNAs RsmY and RsmZ, which sequester CsrA and relieve post-transcriptional repression. LAI-1 produced by LqsA is detected by and prevents phosphorylation of the sensor kinases LqsS and LqsT. Thus, the cognate response regulator LqsR is dephosphorylated. LqsR is positively regulated by RpoS and negatively regulated by the LetA-RsmYZ-CsrA cascade. The response regulators PmrA and CpxR regulate the production of Icm/Dot components and substrates. The signals triggering the sensor histidine kinases LetS, PmrB, and CpxA are not known. Solid and dashed lines represent known/direct or hypothetical/indirect regulation, respectively.