Toll-like receptor 2 deficiency increases resistance to Pseudomonas aeruginosa pneumonia in the setting of sepsis-induced immune dysfunction.
BACKGROUND
Sepsis is characterized by a dysregulated inflammatory response followed by immunosuppression that favors the development of secondary infections. Toll-like receptors (TLRs) are major regulators of the host's response to infections. How variability in TLR signaling may impact the development of sepsis-induced immune dysfunction has not been established. We sought to establish the role of TLR2, TLR4, and TLR5 in postseptic mice with Pseudomonas aeruginosa pneumonia.


METHODS
We used an experimental model of sublethal polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wild-type, tlr2(-/-), tlr4(-/-), tlr5(-/-), tlr2 4(-/-) mice that underwent CLP were secondarily subjected to P. aeruginosa pulmonary infection.


RESULTS
Postseptic wild-type and tlr4(-/-) and tlr5(-/-) mice displayed high susceptibility to P. aeruginosa pneumonia. In contrast, TLR2-deficient mice, either tlr2(-/-)or tlr2 4(-/-), that underwent CLP were resistant to the secondary pulmonary infection. As compared to wild-type mice, tlr2(-/-) mice displayed improvement in bacterial clearance, decreased bacteremic dissemination, and attenuated lung damage. Furthermore, tlr2(-/-) mice exhibited a pulmonary proinflammatory cytokine balance, with increased production of tumor necrosis factor α and decreased release of interleukin 10.


CONCLUSIONS
In a model of secondary P. aeruginosa pneumonia in postseptic mice, TLR2 deficiency improves survival by promoting efficient bacterial clearance and restoring a proinflammatory cytokine balance in the lung.
Inserm U1016, Institut Cochin, France.
Frédéric
F
Pène
David
D
Grimaldi
Benjamin
B
Zuber
Bertrand
B
Sauneuf
Christophe
C
Rousseau
Carole
C
El Hachem
Clémence
C
Martin
Nadia
N
Belaïdouni
Viviane
V
Balloy
Jean-Paul
JP
Mira
Jean-Daniel
JD
Chiche
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005260:Female; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000382:microbiology*; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000276:immunology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000150:complications* / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism
C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D012313:RNA