Staphylococcus aureus skin infections have emerged as a major public health threat in the U.S. as a result the dramatic increase in incidence and the ongoing emergence of methicillin-resistant S. aureus (MRSA) and multi-drug resistant strains. This application will focus on investigating mechanisms of neutrophil recruitment and host defense against S. aureus skin infections and using the information gained from understanding these pathways to develop innovative therapeutic strategies. Based on our published findings and preliminary data, we hypothesize that a major pathway by which the innate immune system combats S. aureus skin infections involves pathogen recognition by Toll-like receptors (TLRs), secretion of IL-1 followed by induction of IL-23/IL-17, which subsequently triggers neutrophil recruitment to the skin. We further hypothesize that different components of this pathway can serve as therapeutic targets against S. aureus skin infections. To test these hypotheses, an in vivo mouse cutaneous S. aureus skin infection model in combination with in vivo imaging techniques to track both the neutrophil recruitment and bacterial clearance in real-time will be used. In addition, innovative human skin culture systems, including cultures of specific innate immune cell populations derived directly from human skin, organotypic keratinocytes, and full thickness human skin explants in combination with human neutrophil chemotaxis assays will be used to determine the predominant cytokines and chemokines that promote neutrophil recruitment in the context of S. aureus infection. Lastly, novel therapeutic strategies will be developed that target human resident skin innate immune cell populations to enhance production of those mediators found to be important in triggering neutrophil recruitment. This application will provide important new insights into mechanisms of neutrophil recruitment and host defense S. aureus skin infections. Furthermore, this study has significant translational potential, since the development of innovative therapeutic strategies to engage the host's neutrophilic response will provide the groundwork for future prevention and treatment interventions against S. aureus skin infection. We believe that this application is timely and relevant, since the need for new and effective treatment modalities are desperately needed to help combat these infections, which are becoming increasingly resistant to antibiotic therapy.

Public Health Relevance

. Staphylococcus aureus skin infections represent a major public health threat in the U.S. as a result of the dramatic increased incidence of these infections and the widespread emergence of virulent and antibiotic- resistant strains. The ultimate objective of this application is to uncover novel insights into mechanisms of host defense against S. aureus skin infection and to use these insights to develop innovative immune-based therapeutic strategies that will provide the groundwork for future prevention and treatment interventions against S. aureus skin infections. We believe that this area of research is highly significant, since the need for new and effective treatment modalities are desperately needed to help combat these infections, which are becoming increasingly resistant to antibiotic therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078910-04
Application #
8213386
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Huntley, Clayton C
Project Start
2009-02-01
Project End
2012-09-06
Budget Start
2012-02-01
Budget End
2012-09-06
Support Year
4
Fiscal Year
2012
Total Cost
$339,605
Indirect Cost
$119,083
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bernthal, Nicholas M; Taylor, Brad N; Meganck, Jeffrey A et al. (2014) Combined in vivo optical and ┬ÁCT imaging to monitor infection, inflammation, and bone anatomy in an orthopaedic implant infection in mice. J Vis Exp :e51612
Stavrakis, Alexandra I; Niska, Jared A; Shahbazian, Jonathan H et al. (2014) Combination prophylactic therapy with rifampin increases efficacy against an experimental Staphylococcus epidermidis subcutaneous implant-related infection. Antimicrob Agents Chemother 58:2377-86
Niska, Jared A; Shahbazian, Jonathan H; Ramos, Romela Irene et al. (2013) Vancomycin-rifampin combination therapy has enhanced efficacy against an experimental Staphylococcus aureus prosthetic joint infection. Antimicrob Agents Chemother 57:5080-6
Guo, Yi; Ramos, Romela Irene; Cho, John S et al. (2013) In vivo bioluminescence imaging to evaluate systemic and topical antibiotics against community-acquired methicillin-resistant Staphylococcus aureus-infected skin wounds in mice. Antimicrob Agents Chemother 57:855-63
Krishna, Sheila; Miller, Lloyd S (2012) Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin Immunopathol 34:261-80
Krishna, Sheila; Miller, Lloyd S (2012) Host-pathogen interactions between the skin and Staphylococcus aureus. Curr Opin Microbiol 15:28-35
Niska, Jared A; Shahbazian, Jonathan H; Ramos, Romela Irene et al. (2012) Daptomycin and tigecycline have broader effective dose ranges than vancomycin as prophylaxis against a Staphylococcus aureus surgical implant infection in mice. Antimicrob Agents Chemother 56:2590-7
Pribaz, Jonathan R; Bernthal, Nicholas M; Billi, Fabrizio et al. (2012) Mouse model of chronic post-arthroplasty infection: noninvasive in vivo bioluminescence imaging to monitor bacterial burden for long-term study. J Orthop Res 30:335-40
Bernthal, Nicholas M; Pribaz, Jonathan R; Stavrakis, Alexandra I et al. (2011) Protective role of IL-1? against post-arthroplasty Staphylococcus aureus infection. J Orthop Res 29:1621-6
Miller, Lloyd S; Cho, John S (2011) Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol 11:505-18

Showing the most recent 10 out of 16 publications