The resurgence of serious group A streptococcal disease which includes sepsis, toxic shock and necrotizing fasciitis has been thoroughly documented. Although other serotypes are associated with these complications, epidemiological data argue that the serotype M1 inv+ subclone was responsible for the increased incidence of toxic shock in the 1990s. Our laboratory was the first to identify the M1 clonal variant that ultimately spread to at least five continents. The overall goal of this project is to understand the role of intracellular invasion of epithelial cells in the persistence and dissemination of highly virulent strains of group A streptococci in human populations. Much of the study will focus on the molecular interactions between M protein-extracellular matrix proteins laminin and fibronectin and the epithelial cell. Experiments will define the role of M1 protein and other bacteriophage and chromosomally encoded proteins in high frequency invasion of human cells. Invasin-agonist functions will be analyzed separate from other streptococcal factors using latex beads and scanning electron microscopy. Finally, in vitro requirements for high frequency invasion will be validated using tonsil organ cultures. These studies may provide an explanation for the failure of penicillin to eradicate streptococci from the oral mucosa of children with recurrent infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI034503-05
Application #
2757762
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Rubin, Fran A
Project Start
1994-12-01
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Wang, Beinan; Yurecko, Ryan S; Dedhar, Shoukat et al. (2006) Integrin-linked kinase is an essential link between integrins and uptake of bacterial pathogens by epithelial cells. Cell Microbiol 8:257-66
Wang, Beinan; Li, Shaoying; Southern, Peter J et al. (2006) Streptococcal modulation of cellular invasion via TGF-beta1 signaling. Proc Natl Acad Sci U S A 103:2380-5
Rezcallah, Myrna S; Hodges, Kimberly; Gill, Darcy B et al. (2005) Engagement of CD46 and alpha5beta1 integrin by group A streptococci is required for efficient invasion of epithelial cells. Cell Microbiol 7:645-53
Zimmerlein, Bjorn; Park, Hae-Sun; Li, Shaoying et al. (2005) The M protein is dispensable for maturation of streptococcal cysteine protease SpeB. Infect Immun 73:859-64
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Purushothaman, Sai Sudha; Wang, Beinan; Cleary, P Patrick (2003) M1 protein triggers a phosphoinositide cascade for group A Streptococcus invasion of epithelial cells. Infect Immun 71:5823-30
Park, Hae-Sun; Francis, Kevin P; Yu, Jun et al. (2003) Membranous cells in nasal-associated lymphoid tissue: a portal of entry for the respiratory mucosal pathogen group A streptococcus. J Immunol 171:2532-7
Cue, D; Lam, H; Cleary, P P (2001) Genetic dissection of the Streptococcus pyogenes M1 protein: regions involved in fibronectin binding and intracellular invasion. Microb Pathog 31:231-42

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