1. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection
- Author
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Molofsky, Ari B, Byrne, Brenda G, Whitfield, Natalie N, Madigan, Cressida A, Fuse, Etsu T, Tateda, Kazuhiro, and Swanson, Michele S
- Subjects
Biodefense ,Infectious Diseases ,Prevention ,Vaccine Related ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Adaptor Proteins ,Signal Transducing ,Animals ,Apoptosis ,Cells ,Cultured ,Cytosol ,Female ,Flagellin ,Immunity ,Innate ,Legionella pneumophila ,Macrophages ,Mice ,Mice ,Inbred A ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myeloid Differentiation Factor 88 ,Neuronal Apoptosis-Inhibitory Protein ,Signal Transduction ,Toll-Like Receptors ,Medical and Health Sciences ,Immunology - Abstract
To restrict infection by Legionella pneumophila, mouse macrophages require Naip5, a member of the nucleotide-binding oligomerization domain leucine-rich repeat family of pattern recognition receptors, which detect cytoplasmic microbial products. We report that mouse macrophages restricted L. pneumophila replication and initiated a proinflammatory program of cell death when flagellin contaminated their cytosol. Nuclear condensation, membrane permeability, and interleukin-1beta secretion were triggered by type IV secretion-competent bacteria that encode flagellin. The macrophage response to L. pneumophila was independent of Toll-like receptor signaling but correlated with Naip5 function and required caspase 1 activity. The L. pneumophila type IV secretion system provided only pore-forming activity because listeriolysin O of Listeria monocytogenes could substitute for its contribution. Flagellin monomers appeared to trigger the macrophage response from perforated phagosomes: once heated to disassemble filaments, flagellin triggered cell death but native flagellar preparations did not. Flagellin made L. pneumophila vulnerable to innate immune mechanisms because Naip5+ macrophages restricted the growth of virulent microbes, but flagellin mutants replicated freely. Likewise, after intratracheal inoculation of Naip5+ mice, the yield of L. pneumophila in the lungs declined, whereas the burden of flagellin mutants increased. Accordingly, macrophages respond to cytosolic flagellin by a mechanism that requires Naip5 and caspase 1 to restrict bacterial replication and release proinflammatory cytokines that control L. pneumophila infection.
- Published
- 2006