During the previous funding cycle, our program project entitled ?Staphylococcal biofilm and disease? has employed in-depth mechanistic approaches to define the developmental and metabolic processes important in Staphylococcus aureus biofilm development. A key aspect of the synergy of this project is that the knowledge gained was used as context to provide a more detailed understanding of the acquisition of available nutrients within specific host niches, as well as the impact of biofilm growth on the host immune response. These studies have led to a greatly enhanced understanding of the way in which S. aureus adapts to a host environment, providing new fundamental insight into biofilm development and novel approaches to the clinical management of staphylococcal disease. The overall hypothesis driving the goals of the proposed program project, S. aureus biofilm development creates unique metabolic niches that promote an immune suppressive environment, is a natural outgrowth of the current funding cycle and is tested in four synergistic and complementary projects that encompass a broad spectrum of synergistic and highly collaborative activities ranging from the basic biology of biofilm development and matrix regulation, to the host-associated metabolic processes that influence the immune response. To support the efforts of these four projects, we propose a continuation of our Bioimaging Core that maintains a BioFlux microfluidics system for biofilm growth and analysis, confocal microscopy, and an In Vivo Imaging System (IVIS). In addition, we propose a new Metabolomics Core that will establish and maintain the protocols and modeling needed to support the four projects associated with this PPG. Importantly, our vision is that the work of this core will lead to the development of a web-based metabolomics tool (funded through a separate mechanism) that will serve not only as an education tool to enhance the overall understanding of the S. aureus metabolome, but also as a hypothesis generator in support of scientific inquiry. Once this tool is established and validated, we will then make it available to the entire staphylococcal research community as a web-based resource that is integrated with our existing Nebraska Transposon Mutant Library (NTML) website. Finally, we propose an Administrative Core that will provide the administrative support needed to maximize the interactions between project leaders and to ensure that their projects maintain optimal synergy.

Public Health Relevance

As a leading cause of indwelling medical device-related infections, the study of Staphylococcus aureus biofilm formation and its impact on its host is critical to reducing the burden of this pervasive pathogen to our healthcare system. The collaborative efforts of our studies seek to identify the mechanisms responsible for the alteration of the host immune response to favor an anti-inflammatory environment that is more permissive for bacterial persistence. Overall, the results of these studies hold promise for the development of improved strategies to treat S. aureus biofilm-related infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083211-12
Application #
9970360
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Huntley, Clayton C
Project Start
2009-07-01
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Yamada, Kelsey J; Kielian, Tammy (2018) Biofilm-Leukocyte Cross-Talk: Impact on Immune Polarization and Immunometabolism. J Innate Immun :1-9
Bhinderwala, Fatema; Lonergan, Samantha; Woods, Jade et al. (2018) Expanding the Coverage of the Metabolome with Nitrogen-Based NMR. Anal Chem 90:4521-4528
Heim, Cortney E; Vidlak, Debbie; Odvody, Jessica et al. (2018) Human prosthetic joint infections are associated with myeloid-derived suppressor cells (MDSCs): Implications for infection persistence. J Orthop Res 36:1605-1613
Svechkarev, Denis; Sadykov, Marat R; Bayles, Kenneth W et al. (2018) Ratiometric Fluorescent Sensor Array as a Versatile Tool for Bacterial Pathogen Identification and Analysis. ACS Sens 3:700-708
Yamada, Kelsey J; Heim, Cortney E; Aldrich, Amy L et al. (2018) Arginase-1 Expression in Myeloid Cells Regulates Staphylococcus aureus Planktonic but Not Biofilm Infection. Infect Immun 86:
King, Alyssa N; Borkar, Samiksha; Samuels, David J et al. (2018) Guanine limitation results in CodY-dependent and -independent alteration of Staphylococcus aureus physiology and gene expression. J Bacteriol :
Mlynek, Kevin D; Sause, William E; Moormeier, Derek E et al. (2018) Nutritional Regulation of the Sae Two-Component System by CodY in Staphylococcus aureus. J Bacteriol 200:
Gries, Casey M; Kielian, Tammy (2017) Staphylococcal Biofilms and Immune Polarization During Prosthetic Joint Infection. J Am Acad Orthop Surg 25 Suppl 1:S20-S24
Krute, Christina N; Rice, Kelly C; Bose, Jeffrey L (2017) VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System. J Bacteriol 199:
Moormeier, Derek E; Bayles, Kenneth W (2017) Staphylococcus aureus biofilm: a complex developmental organism. Mol Microbiol 104:365-376

Showing the most recent 10 out of 105 publications