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-1β 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.
Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection
Abbreviations used: ASC, apoptosis-associated specklike protein; CFP, crude flagellar preparation; LDH, lactate dehydrogenase; LLO, listeriolysin O; LRR, leucine-rich repeat; MOI, multiplicity of infection; NOD, nucleotide-binding oligomerization domain; PAMP, pathogen-associated molecular pattern; PE, postexponential; TLR, Toll-like receptor.
C.A. Madigan's present address is Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115.
Ari B. Molofsky, Brenda G. Byrne, Natalie N. Whitfield, Cressida A. Madigan, Etsu T. Fuse, Kazuhiro Tateda, Michele S. Swanson; Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection . J Exp Med 17 April 2006; 203 (4): 1093–1104. doi: https://doi.org/10.1084/jem.20051659
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