Streptococcus pyogenes or group A Streptococcus (GAS) is an important cause of human disease worldwide. GAS are responsible for millions of cases annually of pharyngitis, skin and soft tissue infections, as well as less common but often life-threatening invasive infections. In addition, GAS have the unique capacity to trigger the postinfectious syndromes of acute rheumatic fever and glomerulonephritis. Clinical epidemiologic observations have associated mucoid, or highly encapsulated, strains of GAS both with invasive infections and with rheumatic fever, suggesting the capsular polysaccharide acts as a virulence factor. Direct evidence supporting this hypothesis was obtained during the previous funding period through studies of acapsular GAS mutants, derived by transposon mutagenesis. Loss of expression of the hyaluronic acid capsule resulted in loss of virulence in mice and loss of resistance to phagocytic killing by human blood leukocytes. The overall objective of the project during the next funding period is to define, at a molecular level, both the regulation of capsule expression and the mechanism through which the GAS capsule modulates the interaction of the organism with the host immune system.
Three specific aims are proposed to achieve this objective. First, the chromosomal region encoding genes of capsule synthesis will be further characterized. These studies will define the boundaries of the capsule gene region surrounding the hyaluronate synthase locus, identify additional genes within the region, and investigate the role of a putative ATP-binding transport system in capsule expression. Second, the molecular basis of regulation of capsule expression will be elucidated by characterizing regulatory sequences upstream of the hyaluronate synthase locus. A chloramphenicol acetyl transferase reporter system will be used to measure the effects of environmental signals on expression of capsule genes and to determine whether polymorphisms of regulatory sequences are correlated with biologically important differences in regulation of capsule expression. Finally, acapsular mutants will be created by marker exchange mutagenesis of the hyaluronate synthase gene. These mutants will be used to accomplish the third aim, to determine the mechanism through which the hyaluronic acid capsule acts as a virulence factor. Studies in this aim will investigate the effects of the capsule on binding of complement component C3 to the bacterial surface, and in modulating the interaction of the bacterial cell with host phagocytes. Results of these studies will advance our understanding of the pathogenesis of streptococcal diseases and may suggest better approaches to prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029952-06
Application #
2442477
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1991-07-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Hancz, Dóra; Westerlund, Elsa; Bastiat-Sempe, Benedicte et al. (2017) Inhibition of Inflammasome-Dependent Interleukin 1? Production by Streptococcal NAD+-Glycohydrolase: Evidence for Extracellular Activity. MBio 8:
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Jiang, Shengmei; Wessels, Michael R (2014) BsaB, a novel adherence factor of group B Streptococcus. Infect Immun 82:1007-16
O'Seaghdha, Maghnus; Wessels, Michael R (2013) Streptolysin O and its co-toxin NAD-glycohydrolase protect group A Streptococcus from Xenophagic killing. PLoS Pathog 9:e1003394
Love, John F; Tran-Winkler, Hien J; Wessels, Michael R (2012) Vitamin D and the human antimicrobial peptide LL-37 enhance group a streptococcus resistance to killing by human cells. MBio 3:
Logsdon, Lauren K; Hakansson, Anders P; Cortes, Guadalupe et al. (2011) Streptolysin O inhibits clathrin-dependent internalization of group A Streptococcus. MBio 2:e00332-10
Tran-Winkler, Hien J; Love, John F; Gryllos, Ioannis et al. (2011) Signal transduction through CsrRS confers an invasive phenotype in group A Streptococcus. PLoS Pathog 7:e1002361

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