Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection.
Streptococcus pneumoniae is a major cause of pneumonia in infants and the elderly. Innate defenses are essential to the control of pneumococcal infections, and deficient responses can trigger disease in susceptible individuals. Here we showed that flagellin can locally activate innate immunity and thereby increase the resistance to acute pneumonia. Flagellin mucosal treatment improved S. pneumoniae clearance in the lungs and promoted increased survival of infection. In addition, lung architecture was fully restored after the treatment of infected mice, indicating that flagellin allows the reestablishment of steady-state conditions. Using a flagellin mutant that is unable to signal through Toll-like receptor 5 (TLR5), we established that TLR5 signaling is essential for protection. In the respiratory tract, flagellin induced neutrophil infiltration into airways and upregulated the expression of genes coding for interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), CXCL1, CXCL2, and CCL20. Using depleting antibodies, we demonstrated that neutrophils are major effectors of protection. Further, we found that B- and T-cell-deficient SCID mice clear S. pneumoniae challenge to the same extent as immunocompetent animals, suggesting that these cell populations are not required for flagellin-induced protection. In conclusion, this study emphasizes that mucosal stimulation of innate immunity by a TLR not naturally engaged by S. pneumoniae can increase the potential to cure pneumococcal pneumonia.
Muñoz
Natalia
N
Department of Biotechnology, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Van Maele
Laurye
L
Marqués
Juan M
JM
Rial
Analía
A
Sirard
Jean-Claude
JC
Chabalgoity
José A
JA
D000281:Administration, Intranasal; D000818:Animals; D001402:B-Lymphocytes; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018893:Bronchoalveolar Lavage; D005260:Female; D005408:Flagellin / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D008168:Lung / Q000166:cytology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009154:Mutation; D009297:Nasal Mucosa / Q000276:immunology; D009504:Neutrophils / Q000502:physiology; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes; D051198:Toll-Like Receptor 5 / Q000502:physiology
D001428:Bacterial Vaccines; D051198:Toll-Like Receptor 5; D005408:Flagellin