Streptococcus agalactiae (Group B streptococci, GBS) are p-hemolytic, gram-positive cocci that cause invasive infections in human neonates and adults. Despite significant advances in prevention and treatment of early onset neonatal disease, rates of GBS-related still births, prematurity, late onset neonatal disease and adult infections are not decreased or prevented. These observations emphasize the importance of alternate strategies for prevention of GBS infections. GBS encounters a wide array of host environments during its disease cycle. Hence, it is essential for the pathogen to rapidly adapt to changing external environments to survive and establish successful infections. Bacterial two component signaling (TCS) systems are critical for pathogens to mediate their adaptive responses to the external/host environment. A TCS composed of a sensor kinase CsrS and a response regulator CsrR regulate expression of GBS cytotoxins i.e. p-hemolysin (P-H/C) and CAMP factor. Our studies have shown that GBS also encodes two eukaryotic-type signaling enzymes comprising a sensor kinase Stk1 and its cognate phosphatase Stp1 that regulate virulence. This proposal seeks to extend our understanding of eukaryotic-type signaling in GBS. Our studies show that the eukaryotic-type kinase Stk1 regulates the expression of GBS cytotoxins (P-H/C and CAMP factor) in a manner that is opposite to the TCS, CsrR/CsrS. Our observation that Stk1 requires CsrR for regulation of cytotoxin expression demonstrates a link between eukaryotic-type and two-component signaling in GBS. The objective of this proposal is to elucidate the interaction between Stk1 and CsrR for adaptive gene expression in GBS. In this proposal, we will also define the role of the cognate signaling components Stp1 and CsrS that regulate Stk1 and CsrR activity, respectively. The three specific aims proposed will 1) define the role of Stp1 on Stk1 regulation of CsrR activity 2) establish the effect of the interaction between Stk1 and CsrR on the ability of CsrS to activate CsrR and 3) determine the functional consequence of Stk1 regulation of CsrR activity. A combination of genetic, molecular, biochemical and proteomic approaches are proposed to elucidate the link between eukaryotic-type and two component signaling mechanisms in GBS. These studies will broaden our understanding on signaling mechanisms employed by GBS to mediate its adaptive responses. This work will provide the foundation for future studies on adaptive gene expression by GBS for survival in various host niches and for evaluation of these signaling components as targets in antimicrobial strategies. Our findings will also have widespread implications on novel mechanisms of signaling that regulate adaptive responses in other pathogenic and non-pathogenic microbes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Seattle Children's Hospital
United States
Zip Code
Vornhagen, Jay; Burnside, Kellie; Whidbey, Christopher et al. (2015) Kinase Inhibitors that Increase the Sensitivity of Methicillin Resistant Staphylococcus aureus to ?-Lactam Antibiotics. Pathogens 4:708-21
Whidbey, Christopher; Harrell, Maria Isabel; Burnside, Kellie et al. (2013) A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta. J Exp Med 210:1265-81
Patras, Kathryn A; Wang, Nai-Yu; Fletcher, Erin M et al. (2013) Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization. Cell Microbiol 15:1154-67
Burnside, Kellie; Rajagopal, Lakshmi (2012) Regulation of prokaryotic gene expression by eukaryotic-like enzymes. Curr Opin Microbiol 15:125-31
Burnside, Kellie; Lembo, Annalisa; Harrell, Maria Isabel et al. (2012) Vaccination with a UV-irradiated genetically attenuated mutant of Staphylococcus aureus provides protection against subsequent systemic infection. J Infect Dis 206:1734-44
Burnside, Kellie; Rajagopal, Lakshmi (2011) Aspects of eukaryotic-like signaling in Gram-positive cocci: a focus on virulence. Future Microbiol 6:747-61
Burnside, Kellie; Lembo, Annalisa; Harrell, Maria Isabel et al. (2011) Serine/threonine phosphatase Stp1 mediates post-transcriptional regulation of hemolysin, autolysis, and virulence of group B Streptococcus. J Biol Chem 286:44197-210
Vega, Carolina; Chou, Seemay; Engel, Katherine et al. (2011) Structure and substrate recognition of the Staphylococcus aureus protein tyrosine phosphatase PtpA. J Mol Biol 413:24-31
Burnside, Kellie; Lembo, Annalisa; de Los Reyes, Melissa et al. (2010) Regulation of hemolysin expression and virulence of Staphylococcus aureus by a serine/threonine kinase and phosphatase. PLoS One 5:e11071
Lembo, Annalisa; Gurney, Michael A; Burnside, Kellie et al. (2010) Regulation of CovR expression in Group B Streptococcus impacts blood-brain barrier penetration. Mol Microbiol 77:431-43

Showing the most recent 10 out of 13 publications