Lipids derived from virulent Francisella tularensis broadly inhibit pulmonary inflammation via toll-like receptor 2 and peroxisome proliferator-activated receptor α.
Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes an acute lethal respiratory disease in humans. The heightened virulence of the pathogen is linked to its unique ability to inhibit Toll-like receptor (TLR)-mediated inflammatory responses. The bacterial component and mechanism of this inhibition are unknown. Here we show that lipids isolated from virulent but not attenuated strains of F. tularensis are not detected by host cells, inhibit production of proinflammatory cytokines by primary macrophages in response to known TLR ligands, and suppress neutrophil recruitment in vivo. We further show that lipid-mediated inhibition of inflammation is dependent on TLR2, MyD88, and the nuclear hormone and fatty acid receptor peroxisome proliferator-activated receptor α (PPARα). Pathogen lipid-mediated interference with inflammatory responses through the engagement of TLR2 and PPARα represents a novel manipulation of host signaling pathways consistent with the ability of highly virulent F. tularensis to efficiently evade host immune responses.
Immunity to Pulmonary Pathogens Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA.
Deborah D
DD
Crane
Robin
R
Ireland
Joshua B
JB
Alinger
Pamela
P
Small
Catharine M
CM
Bosio
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005604:Francisella tularensis / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000302:isolation & purification; D008055:Lipids / Q000276:immunology* / Q000302:isolation & purification; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000276:immunology
D016207:Cytokines; D007166:Immunosuppressive Agents; D008055:Lipids; D047493:PPAR alpha; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2