This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during invasive staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-?), interferon gamma (IFN-?), interleukin (IL)-6, and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study demonstrated robust saeR/S-mediated IFN-? production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes the relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators. This study provides a foundation for future work to identify the individual contributions of specific saeR/S-regulated factors to the host inflammatory response during staphylococcal disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR020185-08
Application #
8360161
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
8
Fiscal Year
2011
Total Cost
$209,434
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
de Jong, Nienke W M; Ramyar, Kasra X; Guerra, Fermin E et al. (2017) Immune evasion by a staphylococcal inhibitor of myeloperoxidase. Proc Natl Acad Sci U S A 114:9439-9444
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
Hedges, Jodi F; Robison, Amanda; Kimmel, Emily et al. (2016) Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue. Infect Immun 84:1815-25
Guerra, Fermin E; Addison, Conrad B; de Jong, Nienke W M et al. (2016) Staphylococcus aureus SaeR/S-regulated factors reduce human neutrophil reactive oxygen species production. J Leukoc Biol 100:1005-1010
Zurek, Oliwia W; Pallister, Kyler B; Voyich, Jovanka M (2015) Staphylococcus aureus Inhibits Neutrophil-derived IL-8 to Promote Cell Death. J Infect Dis 212:934-8
Pallister, Kyler B; Mason, Sara; Nygaard, Tyler K et al. (2015) Bovine CCL28 Mediates Chemotaxis via CCR10 and Demonstrates Direct Antimicrobial Activity against Mastitis Causing Bacteria. PLoS One 10:e0138084
Hoyt, Teri R; Dobrinen, Erin; Kochetkova, Irina et al. (2015) B cells modulate systemic responses to Pneumocystis murina lung infection and protect on-demand hematopoiesis via T cell-independent innate mechanisms when type I interferon signaling is absent. Infect Immun 83:743-58
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; Noon, Brigit; Mohigmi, Mohammad J et al. (2014) Real-time digitization of metabolomics patterns from a living system using mass spectrometry. J Am Soc Mass Spectrom 25:1755-62

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