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PMID: 16606669 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection.

The Journal of experimental medicine ·Vol. 203 ·No. 4 ·2006-04-17 ·Pages 1093-104

Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, Tateda K, Swanson MS

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Animals Apoptosis/physiology Cells, Cultured Cytosol/immunology Female Flagellin/immunology Immunity, Innate Legionella pneumophila/immunology Macrophages/immunology,microbiology Mice Mice, Inbred A Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Myeloid Differentiation Factor 88 Neuronal Apoptosis-Inhibitory Protein/physiology Signal Transduction/physiology Toll-Like Receptors/physiology
Chemicals
Adaptor Proteins, Signal Transducing Myd88 protein, mouse Myeloid Differentiation Factor 88 Naip5 protein, mouse Neuronal Apoptosis-Inhibitory Protein Toll-Like Receptors Flagellin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Molofsky Ari B
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Byrne Brenda G
Whitfield Natalie N
Madigan Cressida A
Fuse Etsu T
Tateda Kazuhiro
Swanson Michele S
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20051659
Published
2006-04-17
Epub
2006-00-10
Pages
1093-104
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC1584282
Subset
IM
Grants
NIAID NIH HHS · R01 AI040694 · United States
NIGMS NIH HHS · T32 GM007315 · United States
NIGMS NIH HHS · T32 GM007544 · United States
NIAID NIH HHS · 2R01 AI040694 · United States
External Links
PubMed source DOI: 10.1084/jem.20051659 PMC Full Text View journal details
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