TLR3 agonist improves survival to secondary pneumonia in a double injury model

Toll-like receptors (TLR) can initiate various immune responses and are therefore activated under diverse infectious states. Previous studies have focused on TLR3 primarily as an antiviral pathway. However, recent research has demonstrated its efficacy in bacterial infection. Having developed a murine double injury model of cecal ligation and puncture (CLP) followed by Pseudomonas aeruginosa (Pa), we hypothesized that targeted administration of Poly I:C, a TLR3 agonist, would protect mice against secondary pneumonia.

B6 mice underwent CLP followed 4 d afterward by an intranasal dose of Pa. Animals were given Poly I:C or vehicle (phosphate-buffered saline) intranasally 24 h post CLP and every day thereafter for a total of 6 d. For acute studies, mice were sacrificed at two time points, 4 d post CLP and 1 d post pneumonia (Pa).

Poly I:C treatment led to a significant improvement in survival (69% versus 33%). Cytokine analysis from bronchioalveolar lavage displayed significant differences both immediately before and after pneumonia. Bronchioalveolar lavage cultures taken at 24 h post double injury showed significantly higher colony counts in the lungs of control animals compared with those of Poly I:C animals. Measurements of TLR3 expression showed significant increases within both the immune and lung epithelial cells of Poly I:C-treated mice. Finally, the lungs of treated animals had significant increases in lymphocytes and innate cells.

The prophylactic treatment applied in this clinically relevant model further illustrates the overarching hypothesis of immune dysfunction and the possibility of corrective immune modulation within the setting of sepsis.