<italic>Legionella pneumophila</italic> regulate flagellar genes that impact macrophage infection.
Molofsky, Ari Benjamin
2005
Abstract
<italic>Legionella pneumophila</italic> is a pathogen that replicates in macrophages and amoebae. As nutrients become limiting, <italic> L. pneumophila</italic> coordinates its differentiation to a transmissive form that is motile, stress resistant, infectious, and cytotoxic to macrophages. For my thesis research, I tested the hypothesis that production of the <italic> L. pneumophila</italic> flagellum impacts its infection of macrophages at multiple levels. First, we find that regulator CsrA is a global repressor of <italic>L. pneumophila</italic> transmission phenotypes, including motility. The two-component system LetA/S relieves CsrA repression to induce transmission traits, many of which are activated by the flagellar sigma factor FliA. For <italic> L. pneumophila</italic> to avoid degradation in macrophages CsrA repression must be relieved by LetA/S before phagocytosis; conversely, before intracellular bacteria can replicate, CsrA repression must be restored. To elucidate how flagellar genes contribute to transmissive traits, we compared the flagellar sigma factor mutant <italic>fliA</italic> with strains whose flagellar construction is disrupted at particular stages. We find that <italic> L. pneumophila</italic> require FliA to avoid destruction in macrophages, whereas motility, flagellar secretion, and external flagellin are not required. Therefore, FliA regulates effector(s) that contribute to the avoidance of lysosomal degradation. Further, only flagellin-expressing microbes induce efficient macrophage cytotoxicity. Thus, the flagellar regulon equips the aquatic pathogen <italic>L. pneumophila</italic> to coordinate motility with multiple traits vital to virulence in host macrophages. To restrict infection by the intracellular pathogen <italic>Legionella pneumophila</italic>, murine macrophages require host Naip5, a member of the NOD-LRR family. We report that murine macrophages commit programmed, pyroptotic cell death when infected by type IV secretion-competent <italic>L. pneumophila </italic> that express flagellin. Flagellin-dependent pyroptotic death correlates with Naip5 function, and is marked by rapid membrane permeability, nuclear condensation, caspase 1 activation, and interleukin-1beta secretion. Naip5<super> +</super> macrophages restrict the intracellular replication of <italic>L. pneumophila</italic> that express flagellin, whereas mutants that lack flagellin replicate freely. We propose that release of flagellin into the macrophage cytosol is detected by Naip5 to activate cellular pathways that restrict <italic> L. pneumophila</italic> infection. Therefore, the <italic>Legionella pneumophila </italic> flagellar machinery promotes macrophage infection, but is also an Achilles' heel, as the immune system is tuned to recognize essential virulence factors such as flagellin.Subjects
Flagellar Genes Impact Infection Legionella Pneumophila Macrophage Regulate
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