Large surface area burns cause loss of the protective skin barrier and dysregulation of antimicrobial defense mechanisms resulting in ideal conditions for colonization of burn wounds and dissemination of bacteria into blood, lung and other tissues. Although topical and systemic antibiotics are routinely used, sepsis is the most common cause of prolonged hospitalization and death in burn patients that survive the initial insult. The frequency and severity of sepsis is exacerbated by the increasing prevalence of antibiotic resistant bacteria. Therefore, there is a need for new treatments to improve resistance to infection in severely burned patients. Our studies show that treatment with the toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) is effective in improving innate host resistance to Pseudomonas aeruginosa burn wound sepsis in mice. MPLA has low toxicity and is currently used widely as a vaccine adjuvant in the clinical setting. However, the mechanisms by which MPLA augments the host response to systemic bacterial infections are not well understood and further work is needed to translate the use of MPLA in high risk patients to the clinical setting. The goal of this project is to identify the cellular and molecular mechanisms by which TLR4-targeted immunomodulators, such as MPLA, improve innate host resistance to infection in high risk subjects. Pre-clinical studies will establish the safety and efficacy of MPLA in large animal models of burn wound infection and post-burn pneumonia.
Specific Aim 1 : To define the cellular mechanisms by which MPLA augments innate antimicrobial functions.
This aim will test the hypothesis that treatment with MPLA will improve the response to infection after burn injury by inducing G-CSF-mediated expansion of the bone marrow neutrophil pool and causing augmentation of neutrophil chemotaxis.
Specific aim 2 : To define intracellular signaling alterations by which MPLA augments resistance to infection.
This aim will test the hypothesis that MPLA treatment will cause alterations in infection-induced signaling resulting in predominance of the protective PI3K and Trif/IRF-3/IFN? pathways.
Specific Aim 3 : To determine the safety and efficacy of MPLA in an ovine model of burn wound infection and post-burn pneumonia.
This aim will test the hypothesis that MPLA will be well tolerated in burned sheep and will improve their response to wound infection and pneumonia. The results gained in the proposed studies will facilitate the translation of TLR4-targeted immunomodulators into the clinical setting and will fill important gaps in knowledge by advancing our understanding of the cellular and molecular mechanisms by which TLR-based immunomodulators improve host resistance to infections.

Public Health Relevance

Infection is a major cause of death in critically ill patients. The information gained from this project will advance our ability to use TLR4-based immunomodulators to prevent infections in high risk patients and fill important gaps in knowledge by improving our understanding of how TLR-based immunomodulators work.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-J (02))
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Dunsmore, Sarah
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Vanderbilt University Medical Center
Schools of Medicine
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Fensterheim, Benjamin A; Young, Jamey D; Luan, Liming et al. (2018) The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism. J Immunol 200:3777-3789
Stark, Ryan J; Koch, Stephen R; Choi, Hyehun et al. (2018) Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling. FASEB J 32:945-956
Koch, Stephen R; Lamb, Fred S; Hellman, Judith et al. (2017) Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Transl Res 180:53-67.e4
Fensterheim, Benjamin A; Guo, Yin; Sherwood, Edward R et al. (2017) The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection. J Immunol 198:3264-3273
Luan, Liming; Patil, Naeem K; Guo, Yin et al. (2017) Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A. Sci Rep 7:40050
Guo, Yin; Luan, Liming; Patil, Naeem K et al. (2017) IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function. J Immunol 198:1320-1333
Hernandez, Antonio; Bohannon, Julia K; Luan, Liming et al. (2016) The role of MyD88- and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes. J Leukoc Biol 100:1311-1322
Bohannon, Julia K; Luan, Liming; Hernandez, Antonio et al. (2016) Role of G-CSF in monophosphoryl lipid A-mediated augmentation of neutrophil functions after burn injury. J Leukoc Biol 99:629-40
Stark, Ryan J; Choi, Hyehun; Koch, Stephen R et al. (2016) Endothelial cell tolerance to lipopolysaccharide challenge is induced by monophosphoryl lipid A. Clin Sci (Lond) 130:451-61
Enkhbaatar, Perenlei; Nelson, Christina; Salsbury, John R et al. (2015) Comparison of Gene Expression by Sheep and Human Blood Stimulated with the TLR4 Agonists Lipopolysaccharide and Monophosphoryl Lipid A. PLoS One 10:e0144345

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