This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Methicillin-resistant Staphylococcus aureus (MRSA) is problematic both in hospitals and in the community and is now a major cause of human mortality, as an estimated 18, 650 deaths were associated with invasive MRSA infections during 2005 in the United States alone. In recent years, there has been an increase in the incidence of community-associated methicillin-resistant S. aureus (CA-MRSA) infections in healthy individuals. These emerging strains cause skin and soft-tissue infections, but the most prominent strains have also been associated with severe pathology, including sepsis, necrotizing pneumonia, and necrotizing fasciitis. The long-term objective of this proposal is to define the pathogen and host factors contributing to invasive staphylococcal disease. To that end, we have investigated the influence of the SaeR/S two-component gene-regulatory system on invasive staphylococcal disease. We hypothesize that cytolytic factors influenced by the SaeR/S regulatory system of S. aureus promote an inflammatory host response, resulting in the severe pathology seen in invasive staphylococcal infection. This hypothesis is based on preliminary findings demonstrating: 1) significantly attenuated survival of a saeR/S mutant strain (MWdelta saeR/S) after PMN phagocytosis;2) absence of mortality and morbidity in a mouse model of invasive infection in mice infected with MWdelta-saeR/S;and 3) evidence of saeR/S altering gene expression in a wide variety of genes with diverse functions including those involved in evasion of phagocytosis, and virulence. Based on these results, three Specific Aims are designed to provide a comprehensive assessment of the role of saeR/S during invasive staphylococcal disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR020185-07
Application #
8168415
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2010-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$207,256
Indirect Cost
Name
Montana State University - Bozeman
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
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Guerra, Fermin E; Borgogna, Timothy R; Patel, Delisha M et al. (2017) Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus. Front Cell Infect Microbiol 7:286
Siemsen, Dan W; Dobrinen, Erin; Han, Soo et al. (2016) Vascular Dysfunction in Pneumocystis-Associated Pulmonary Hypertension Is Related to Endothelin Response and Adrenomedullin Concentration. Am J Pathol 186:259-69
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Prigge, Justin R; Hoyt, Teri R; Dobrinen, Erin et al. (2015) Type I IFNs Act upon Hematopoietic Progenitors To Protect and Maintain Hematopoiesis during Pneumocystis Lung Infection in Mice. J Immunol 195:5347-57
Heinemann, Joshua; Hamerly, Timothy; Maaty, Walid S et al. (2014) Expanding the paradigm of thiol redox in the thermophilic root of life. Biochim Biophys Acta 1840:80-5

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