Pseudomonas aeruginosa is a cause of serious lung infection in cystic fibrosis patients. The receptors on the host cells responsible for the recognition of this bacterium are unclear. Toll-like receptors (TLR) induce distinct patterns of host responses through MyD88-dependent and/or -independent pathways depending upon the nature of the pathogen. Our study examines the specific contribution of TLR2, TLR4 and a TLR adaptor protein MyD88 in the host defense against P. aeruginosa lung infection.
TLR2-deficient mice, TLR4 mutant mice and MyD88-deficient mice were challenged intranasally with cystic fibrosis-associated P. aeruginosa (strain 8821). After 4, 8 or 24 h infection, bronchoalveolar lavage fluids and lung tissues were collected for the examination of bacterial clearance and airway inflammation. Neutrophil recruitment was determined by myeloperoxidase assay and histological examination of the lung. TNF, IL-1 and MIP-2 in the BALF and lung homogenates were determined by ELISA. TLR2 and TLR4 expression in the lung was examined by real-time RT-PCR.
Both TLR2-deficient mice and TLR4 mutant mice showed partial inhibition of neutrophil recruitment into the lung and production of TNF, IL-1 and MIP-2, compared to wild-type mice. Strikingly, MyD88 mice showed near complete inhibition of neutrophil infiltration and production of TNF, IL-1 and MIP2, and an impaired clearance of P. aeruginosa from the lung. Interestingly, P. aeruginosa-infection stimulated TLR2 but not TLR4 expression in the lung.
TLR-MyD88 pathway plays an essential role in the development of host response to P. aeruginosa lung infection. TLR2 and TLR4 are involved in this process. However, additional TLRs or interactions between TLR2 and TLR4 are important for the full development of host defense against this bacterium. The increase of TLR2 expression in the lung suggests that the role for TLR2 may increase as the infection progresses.
Targeting TLRs and their adaptor molecule MyD88 for the development of vaccine or for the regulation of immune response may serve as an additional approach for the management of P. aeruginosa lung infection.
T. Lin, None.