Group B streptococcus (GBS) is currently a leading single cause of neonatal sepsis and the third most frequent over all cause of bacterial meningitis in the United States. Importantly, 50% of children surviving meningitis suffer from long term neurodevelopmental sequelae. Furthermore, GBS is of growing importance as cause of invasive bacterial disease in patients with diabetes. In the outgoing funding period we have defined three principle inflammatory patterns in GBS that essentially contribute to mortality in a neonatal sepsis model. First, we have identified lipoproteins as endotoxins that constitute functional equivalents to the well defined lipopolysaccharide in Gram-negative bacteria. Lipoproteins induce inflammatory cytokines through interaction with the Toll-like-receptors (TLR) 2 and 6. TLR2 furthermore mediates apoptosis of microglia and neurons in response to GBS which likely contributes to the substantial neurological sequelae of GBS meningitis. Second, we have uncovered a GBS cell bound, yet-to-be defined factor that induces cytokine formation in dependence on particle uptake and expression of the TLR-adapter protein MyD88, but cannot be assigned to established modes of TLR recognition. Finally, live GBS engage a TLR- and MyD88-independent pathway that results in the formation of IFN-?. The overall goal of this proposal is to better define the interphase between GBS and phagocytes with respect to GBS recognition and subsequent regulation of the inflammatory response in order to prepare adjunctive therapeutic strategies that target GBS substructures and host cell molecules. Specifically we intend to identify the MyD88-dependent GBS cell wall factor on the molecular level and dissect its most potent effect on the host cell transcription machinery. Next, we plan to define the roles of GBS phagocytosis (or invasion) and modification of GBS inside phagocytes for the inflammatory phenotype. Furthermore, we analyze the nature of interaction between lipoproteins and TLRs and intend to determine, whether and how lipoproteins exert potent apoptotic activity on CNS cells like microglia. Finally, we seek to define the contribution of individual lipoproteins to sepsis pathogenesis in vivo. The data generated by this study should help to better understand why a common colonizer turns into a sepsis pathogen in individual patients. The completion of these studies will allow us to understand how Group B streptococcus, a leading cause of severe bacterial infections in newborn infants, is recognized by the immune system. We believe this will eventually lead to better therapies against this devastating microbe.

Public Health Relevance

Group B streptococcus is a major cause of sickness and death in neonates and infant children, in whom it causes sepsis syndrome and meningitis. The disease is caused by streptococcal molecules activating primitive receptors on leukocytes to over produce inflammatory mediators. The goal of this grant is to identify the streptococcal molecules and the receptors they activate in order to diminish the severity of Group B streptococcal infection in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052455-10
Application #
8241044
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
GU, Xin-Xing
Project Start
2002-08-15
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$426,011
Indirect Cost
$75,358
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
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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
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Santos-Sierra, Sandra; Deshmukh, Sachin D; Kalnitski, Julia et al. (2009) Mal connects TLR2 to PI3Kinase activation and phagocyte polarization. EMBO J 28:2018-27
Wennekamp, Julia; Henneke, Philipp (2008) Induction and termination of inflammatory signaling in group B streptococcal sepsis. Immunol Rev 225:114-27

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