Treatment with TLR4 agonists protect against infection after severe burn injury.

Abstract

Infection is the leading cause of death in severely burned patients. Prophylactic treatment with the TLR4 agonist monophosphoryl lipid A (MPLA) induces resistance to subsequent bacterial challenge. Treatment of mice with MPLA enhances bacterial clearance, leading to improved survival in a model of P. aeruginosa burn wound infection. The current study was aimed to define the mechanisms responsible for improved bacterial clearance and survival in MPLA-treated burn-infected mice, and to determine if MPLA could protect against clinically relevant Gram positive and fungal pathogens. Mice underwent severe burn injury, followed by systemic treatment with MPLA or vehicle control for 2 days. Mice were then inoculated with P. aeruginosa topically or intraperitoneally, and responding neutrophils were measured in bone marrow, blood, burn wound and peritoneal cavity. In later experiments, burned mice were challenged systemically with S. aureus or C. albicans. MPLA treatment induced G-CSF production, decreased bone marrow neutrophil numbers and increased neutrophil numbers in the blood, peritoneal cavity and burn wound site. G-CSF was essential for MPLA-mediated survival, bacterial clearance and neutrophil trafficking. MPLA also improved survival against S. aureus and C. albicans systemic infections after burn. This suggests that G-CSF facilitates MPLA-induced trafficking of neutrophils, allowing for a more rapid response to sites of infection. The ability of MPLA to enhance antimicrobial responses and its ability to protect against a variety of clinically relevant pathogens make it an attractive therapeutic candidate for use in burn patients for the prevention of post-burn infections.