Redundant Toll-like receptor signaling in the pulmonary host response toPseudomonas aeruginosa

Abstract

Activation of pulmonary defenses against Pseudomonas aeruginosa requires myeloid differentiation factor 88 (MyD88), an adaptor for Toll-like receptor (TLR) signaling. To determine which TLRs mediate recognition of P. aeruginosa, we measured cytokine responses of bone marrow cells from wild-type mice and mice lacking TLR2 (TLR2−/−), TLR4 (TLR4−/−), TLR2 and TLR4 (TLR2/4−/−), or MyD88 (MyD88−/−) to wild-type P. aeruginosa and to fliC P. aeruginosa, which lacks the TLR5 ligand flagellin. Mice also were challenged with aerosolized bacteria to determine cytokine responses, lung inflammation, and bacterial clearance. TNF induction required MyD88 and was absent in TLR2/4−/−cells in response to fliC but not wild-type P. aeruginosa, whereas TLR2−/−cells exhibited augmented responses. In vivo, TLR4−/−mice responded to wild-type P. aeruginosa with reduced cytokine production and inflammation, but intact bacterial clearance, while TLR2−/−mice had partially impaired cytokine responses and delayed bacterial killing despite normal inflammation. When challenged with fliC, MyD88−/−mice failed to mount early cytokine and inflammatory responses or control bacterial replication, resulting in necrotizing lung injury and lethal disseminated infection. TLR4−/−and TLR2/4−/−mice responded to fliC infection with severely limited inflammatory and cytokine responses but intact bacterial clearance. TLR2−/−mice had partially reduced cytokine responses but augmented inflammation and preserved bacterial killing. These data indicate that TLR4- and flagellin-induced signals mediate most of the acute inflammatory response to Pseudomonas and that TLR2 has a counterregulatory role. However, MyD88-dependent pathways, in addition to those downstream of TLR2, TLR4, and TLR5, are required for pulmonary defense against P. aeruginosa.

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

“…We and others have previously shown that TLR4 [23,42] as well as TLR5 [24,43] is also involved. Differential engagement of PRR involved in P. aeruginosa recognition could depend on the site or the time of infection and the prevailing microbial ligand.…”

“…In murine experimental models of lung infection triggered by P. aeruginosa, TLR signaling seems redundant in the pulmonary host response [24,25], suggesting potential involvement of another receptor in the host defense against P. aeruginosa.…”

Airway epithelial cell signaling in response to bacterial pathogens

“…Similar results were obtained in a model of post-influenza pneumococcal pneumonia. 20 Similarly, TLR2 null mice did not show increased mortality or developed pneumonia after challenge with the Gram-negative pulmonary pathogen P. aeruginosa by aerosol, 21 indicating that other signaling pathways in addition to TLR2/MyD88 signaling are evidently involved in responses to these pulmonary pathogens.…”

“…[32][33][34][35] MyD88 null mice have a more defined phenotype upon bacterial infection than null mice for any of the individual TLRs. 21,36 This suggests that multiple TLRs contribute to the host response to certain organisms, or that other receptors not yet identified can signal through MyD88 and participate in responses to bacterial infection.…”

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

“…Moreover, studies have suggested the role of TLR5 in induction of an early innate response and of T2SS and T3SS, in death, due to Pseudomonas infection in mouse lung infection model [18,26,27]. …”