TLRs 2 and 4 are not involved in hypersusceptibility to acute Pseudomonas aeruginosa lung infections.
TLRs are implicated in defense against microorganisms. Animal models have demonstrated that the susceptibility to a number of Gram-negative pathogens is linked to TLR4, and thus LPS of many Gram-negative bacteria have been implicated as virulence factors. To assess the role of this pathogen-associated molecular pattern as it is exposed on intact Pseudomonas aeruginosa, the susceptibility of mice lacking TLR4 or both TLR2 and TLR4 was examined in a model of acute Pseudomonas pneumonia. These mutant mice were not hypersusceptible to the Pseudomonas challenge and mounted an effective innate response that cleared the organism despite low levels of TNF-alpha and KC in the airways. Bacterial and neutrophil counts in the lung were similar in control and TLR-deficient mice at 6 and 24 h after infection. MyD88(-/-) mice were, however, hypersusceptible, with 100% of mice dying within 48 h with a lower dose of P. aeruginosa. Of note there were normal levels of IL-6 and G-CSF in the airways of TLR mutant mice that were absent from the MyD88(-/-) mice. Thus, the susceptibility of mice to P. aeruginosa acute lung infection does not go through TLR2 or TLR4, implying that Pseudomonas LPS is not the most important virulence factor in acute pneumonia caused by this organism. Furthermore, G-CSF treatment of infected MyD88(-/-) mice results in improved clearance and survival. Thus, the resistance to infection in TLR2/TLR4(-/-) mice may be linked to G-CSF and possibly IL-6 production.
Ramphal
Reuben
R
Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
Balloy
Viviane
V
Huerre
Michel
M
Si-Tahar
Mustapha
M
Chignard
Michel
M
D000208:Acute Disease; D000818:Animals; D004198:Disease Susceptibility; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008171:Lung Diseases / Q000209:etiology / Q000382:microbiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011552:Pseudomonas Infections / Q000209:etiology*; D011550:Pseudomonas aeruginosa; D051195:Toll-Like Receptor 2 / Q000172:deficiency*; D051197:Toll-Like Receptor 4 / Q000172:deficiency*; D037521:Virulence Factors
D015850:Interleukin-6; D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D037521:Virulence Factors; D016179:Granulocyte Colony-Stimulating Factor