The inflammatory response and the innate immune system serve to 1) recruit immune cells to the wound, 2) contain and kill invading organisms and 3) clear the wound of noxious substances. However, wound infections are commonplace after thermal injuries and represent a major cause of morbidity and mortality. Bacteria that colonize the wound grow as adherent, multicellular communities known as biofilms and the biofilm mode of growth renders the bacterial cells resistant to killing by antiseptics, antibiotics and host defenses, which may explain the nature of many wound infections. Recently we found that exogenously added ATP can stimulate bacteria adherence and biofilm formation on abiotic and biotic surfaces and in a burn wound and previous studies in the literature found that injured epithelial cells release large amount ATP into the extracellular space, which serves as a "danger signal" and activate host innate immunity. Therefore, the major objective of this project is to define the role of extracellular ATP in bacteria-host interactions within the thermal injury. We hypothesize that extracellular ATP severs as an "inter-domain" signal and modulate both bacteria and host responses in the burn wound and can be a target for managing wound infections. To test this hypothesis, we will use both in vitro and in vivo models to elucidate molecular mechanisms of extracellular ATP signaling in bacteria using Acinetobater baumannii and E. coli as model organisms focusing on biofilm development and examine the inflammatory cytokines and leukocyte bacterial killing within thermal injuries by modulating extracellular ATP using the enzyme apyrase. Success of this study will enhance a more comprehensive and basic understanding of bacteria-host interactions and bacterial pathogenesis and will likely lead to the development of novel approaches to prevent/reduce wound infections and other infectious diseases.

Public Health Relevance

The proposed research will investigate the central role of extracellular ATP in regulating both host and bacteria responses in burn wounds and to evaluate the effectiveness of novel approaches for managing wound infections. The study will lead to the development of new therapeutic products for effective control of wound infections and other biofilm related infectious diseases. Success of this project will have a great impact in medicine and on public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098350-04
Application #
8721974
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2011-09-10
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$290,695
Indirect Cost
$100,695
Name
University of Michigan Ann Arbor
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Peterson, Jonathan R; De La Rosa, Sara; Eboda, Oluwatobi et al. (2014) Treatment of heterotopic ossification through remote ATP hydrolysis. Sci Transl Med 6:255ra132
Bayliss, Jill; Delarosa, Sara; Wu, Jianfeng et al. (2014) Adenosine triphosphate hydrolysis reduces neutrophil infiltration and necrosis in partial-thickness scald burns in mice. J Burn Care Res 35:54-61