Submitted on May 11, 2009
Revised on September 28, 2009
Accepted on September 30, 2009
The Role of Toll-Like Receptor 5 in the Innate Immune Response to Acute P. aeruginosa Pneumonia
Amy E. Morris1, H. Denny Liggitt2, Thomas R. Hawn3, and Shawn J. Skerrett4*
1 Harborview Medical Center
2 University of Washington
3 U of Washington
4 U Washington
* To whom correspondence should be addressed. E-mail: shawn{at}u.washington.edu.
P. aeruginosa is a leading cause of hospital-acquired pneumonia and an important pathogen in patients with chronic lung disease such as cystic fibrosis and bronchiectasis. The contribution of toll-like receptor 5 (TLR5) to the innate immune response to this organism is incompletely understood. We exposed wild-type (WT) and Tlr5-/- mice to aerosolized P. aeruginosa at low and high inocula then assessed bacterial clearance, lung inflammation, and cytokine production 4 and 24 hours after infection. Tlr5-/- mice had impaired bacterial clearance after low inoculum, but not high inoculum infection. Early bronchoalveolar accumulation of neutrophils was reduced in Tlr5-/- mice after both low- and high-dose infection. Cytokine responses were selectively altered in TLR5-deficient animals, including markedly impaired MCP-1 production 4 hours after both low- and high-inoculum challenge. In contrast, Tlr5-/- mice had no impairment in bacterial clearance, neutrophil recruitment or MCP-1 production after infection with a nonflagellated isotypic strain of P. aeruginosa. Thus, TLR5-mediated recognition of flagellin is involved in activating pulmonary defenses against P. aeruginosa, and contributes to antibacterial resistance in a manner that is partially inoculum-dependent. These data are the first to demonstrate a unique role for TLR5 in the innate immune response to P. aeruginosa lung infection.
