| dc.description | Toll-like receptors (TLR) induce distinct patterns of innate immune responses through myeloid differentiation factor 88 (MyD88) dependent and/or independent pathways, depending on the nature of the pathogen. Pseudomonas aeruginosa is a cause of serious lung infection in immunocompromised individuals and cystic fibrosis patients. The role of TLR pathways in P. aeruginosa induced lung infection were examined in vivo in this study. MyD88 deficient mice demonstrated a delayed clearance of P. aeruginosa from the lung and a delay in neutrophil recruitment to the airways. These observations were associated with a delay in the production of inflammatory mediators that affect neutrophil recruitment, including macrophage inflammatory protein 2 (CXCL2/MIP-2), tumor necrosis factor (TNF), and interleukin (IL)-1beta in the airways of MyD88 deficient mice. Similarly, in the lung of MyD88 deficient mice nuclear factor kappaB (NFkappaB) activation was inhibited following P. aeruginosa infection. Innate immune responses to P. aeruginosa lung infection in TLR2 deficient and TLR4 mutant mice were partially inhibited compared with the responses of respective control mice. Thus, the full development of host responses to P. aeruginosa lung infection involves a MyD88 dependent and a MyD88 independent mechanism. Toll-IL-1 receptor domain containing adapter inducing IFNbeta (TRIF) is an adaptor molecule that mediates a distinct TLR signaling pathway. The role of TRIF in P. aeruginosa infection was also investigated. Following P. aeruginosa infection, TRIF deficient mice showed a complete inhibition of CCL5/RANTES production, severe impairment in TNF and CXCL1/KC production, but normal CXCL2/MIP-2 and IL-1beta production in the lung. This was associated with a delayed recruitment of neutrophils into the airways. These results demonstrate that TRIF mediates a distinct cytokine/chemokine profile in response to P. aeruginosa infection. Importantly, TRIF deficient mice had a delayed clearance of P. aeruginosa from the lung when compared with wild type mice. Thus, TRIF is an adaptor molecule that is required for the development of the innate immune response to P. aeruginosa infection. These results indicate that the MyD88 and TRIF pathways are essential for the development of innate immune responses to P. aeruginosa infection, leading to the clearance of this bacterium. | en_US |
