Cellular Mechanisms of Immune Dysfunction Following Severe Burn Injury Public Deposited

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Last Modified
  • March 22, 2019
Creator
  • Neely, Crystal J.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The immune system protects the body against infection and disease. Severe burn injury induces profound immune dysfunction rendering patients extremely susceptible to infection. Although progress has been made in reducing the incidence of infection, burn wound infection and pulmonary sepsis are still major causes of mortality. Therefore, in order to improve patient outcome it is important to understand the immune response to infection after burn injury. Furthermore, the immune response following burn injury is dynamic and changes over time. Therefore, elucidating the immune response both early and late after burn is also crucial. Using a murine model of thermal injury, we characterized the pro-inflammatory CD4+ T cell response at various timepoints after burn. We detected Th17 cells in wound-draining lymph nodes at 3, 7, and 14 days post burn. Also, there was bimodal skewing of the Th1/Th17 T cell balance with an early predominance of Th1 cells Th17 cells late. The innate immune response to a clinically relevant pathogen was then assessed early after burn injury. Burn mice were susceptible to an early wound inoculation with Pseudomonas aeruginosa as demonstrated with high mortality rates and bacterial spread systemically. Defective bacterial clearance of P. aeruginosa early after burn injury correlated with polarization of neutrophils into an anti-inflammatory (N2; IL-10+ IL-12-) phenotype. Administration of flagellin after burn injury skewed the neutrophil response towards a pro-inflammatory neutrophil (N1; IL-10-IL-12+) phenotype resulting in increased bacterial clearance. Additional studies evaluated susceptibility to pulmonary P. aeruginosa infection late after burn injury. In contrast to early wound infection, burn mice exhibited enhanced clearance of a delayed pulmonary P. aeruginosa challenge compared to non-burn controls. This appeared to result from to a burn-induced accumulation of neutrophils within the lungs. Collectively, these data suggests that neutrophil responses vary after burn injury where they exhibit an anti-inflammatory phenotype early after burn followed by a late and pro-inflammatory phenotype. This work provides insights into the cellular mechanisms of immune dysfunction following severe burn injury, as well as identifies neutrophil polarization as a novel therapeutic target for the reversal of bacterial susceptibility after injury.
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  • In Copyright
Advisor
  • Cairns, Bruce
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2013
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