As a result of loss of the protective barrier of the skin combined with numerous injury-induced immunological alterations that decrease the ability to clear and control infections, severely burned patients are highly susceptible to opportunistic infections. Infection remains the leading cause of death in patients that survive the initial burn injury. Toll-like receptor 4 agonists lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA) have been shown to have strong immunomodulatory properties. Prior sensitization with low doses of LPS or MPLA is known to induce a state of tolerance to subsequent LPS challenge, which is associated with an enhanced ability to clear bacteria following systemic challenge with Pseudomonas aeruginosa. Whereas LPS has numerous undesirable side effects, MPLA is relatively innocuous and would therefore be more suited for clinical usage to enhance immune responses to infection. Previous studies have shown that treatment of mice with MPLA greatly enhances bacterial clearance after a burn wound infection, leading to increased survival and this clearance is mediated, in part, by increased recruitment of neutrophils to the site of infection. This proposal is designed to test the hypothesis that treatment of burn injured mice with MPLA will result in improved resistance to infection mediated by enhanced antimicrobial immunity, both locally and systemically. Using a mouse model of burn injury and associated infection to test this hypothesis, the following specific aims are proposed:
Aim 1 : To define the cellular mechanisms responsible for MPLA-mediated augmentation of innate antimicrobial responses after burn injury.
This aim will test the sub-hypothesis that MPLA treatment will enhance neutrophil-mediated immune responses to a burn-associated infection.
Aim 2 : To determine the role of TLR4 signaling pathways in facilitating the antimicrobial effects of MPLA.
This aim will test the sub-hypothesis that MPLA-enhancement of neutrophil-mediated antimicrobial responses and improvement in bacterial clearance is dependent upon TLR4- and Trif-mediated activation of the PI3K signaling pathway.
Infection is the leading cause of death in burn patients who survive the initial trauma. This is primarily due to augmentation of the immune response by the burn injury. The knowledge gained from this project will advance our understanding of how TLR4-based immunomodulators can be used as treatments to prevent deadly infections in immunocompromised patients.