Group B streptococci (GBS) are the leading cause of neonatal sepsis, the third most frequent cause of bacterial meningitis and an increasingly important cause of bacteremia and sepsis in adults in the United States today. Preliminary studies have identified a novel proinflammatory component of GBS, which we have designated GBS-factor (GBS-F). Based on experiments in mice with targeted genetic deletions in Toll-like receptor (TLR) expression and on experiments with engineered cell lines, we have determined that responses to GBS-F require expression of CD14, TLRs 2 and 6, and the Toll-adapter protein, MyD88. Activation of this receptor complex by GBS-F initiates important signaling events such as the activation of NF-kB, the phosphorylation of MAP kinases, the formation of proinflammatory cytokines, and the intracellular production of the toxic oxidant peroxynitrate. In contrast, although other components of GBS appear to engage TLRs, the exact identity of contributing TLRs is entirely unknown. The overall goal of this proposal is to identify and define components of GBS, focusing first on GBS-F, and their cognate Toll-like receptors (TLRs). We propose to characterize the structure of GBS-F and assess its function in vitro and in vivo. Furthermore, we will determine if TLR2, and related downstream signal transduction molecules, mediate a variety of important innate immune responses to GBS, including leukocyte chemotaxis and the intracellular killing of bacteria. Finally, we intend to determine what other TLRs, and associated signal transduction molecules, are involved in GBS recognition and response. The data learned from these studies should help in the development of rational therapeutic strategies to interfere with the deleterious hyperinflammation triggered by GBS and similar microbial organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052455-04
Application #
6929043
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Rubin, Fran A
Project Start
2002-08-15
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$418,817
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Gupta, Rahul; Ghosh, Shubhendu; Monks, Brian et al. (2014) RNA and ?-hemolysin of group B Streptococcus induce interleukin-1? (IL-1?) by activating NLRP3 inflammasomes in mouse macrophages. J Biol Chem 289:13701-5
Elling, Roland; Hufnagel, Markus; de Zoysa, Aruni et al. (2014) Synchronous recurrence of group B streptococcal late-onset sepsis in twins. Pediatrics 133:e1388-91
Firon, Arnaud; Tazi, Asmaa; Da Cunha, Violette et al. (2013) The Abi-domain protein Abx1 interacts with the CovS histidine kinase to control virulence gene expression in group B Streptococcus. PLoS Pathog 9:e1003179
Costa, Alessandro; Gupta, Rahul; Signorino, Giacomo et al. (2012) Activation of the NLRP3 inflammasome by group B streptococci. J Immunol 188:1953-60
Deshmukh, Sachin D; Müller, Sabrina; Hese, Katrin et al. (2012) NO is a macrophage autonomous modifier of the cytokine response to streptococcal single-stranded RNA. J Immunol 188:774-80
Saar-Dover, Ron; Bitler, Arkadi; Nezer, Ravit et al. (2012) D-alanylation of lipoteichoic acids confers resistance to cationic peptides in group B streptococcus by increasing the cell wall density. PLoS Pathog 8:e1002891
Levitz, Stuart M; Golenbock, Douglas T (2012) Beyond empiricism: informing vaccine development through innate immunity research. Cell 148:1284-92
Kenzel, Sybille; Mergen, Miriam; von Süßkind-Schwendi, Julius et al. (2012) Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase. J Immunol 189:4582-91
Deshmukh, Sachin D; Kremer, Bernhard; Freudenberg, Marina et al. (2011) Macrophages recognize streptococci through bacterial single-stranded RNA. EMBO Rep 12:71-6
Papasergi, Salvatore; Brega, Sara; Mistou, Michel-Yves et al. (2011) The GBS PI-2a pilus is required for virulence in mice neonates. PLoS One 6:e18747

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