Group A streptococci are still a major cause of illness in children. The resurgence of rheumatic fever and associated heart disease in many communities in the United States in the past two years has reminded the medical community that this pathogen has the potential to initiate serious morbidity. Pathogenic streptococci are covered with a fibrous protein coat which permits them to avoid the human immunological defenses. Like most bacterial pathogens the macromolecular composition of this fibrous layer and the capacity to cause disease is finely regulated and subject to change. Streptococci switch between virulent and avirulent states, a phenomenon termed phase variation. Understanding the molecular basis of phase variation and its role in the infectious process is the ultimate goal of this project. Virulence is dependent on a multitude of factors, antiphagocytic M proteins, and inhibitor of chemotaxis, IgG Fc receptor proteins and a variety of toxins. Our studies showed that expression of M protein is under the control of a reversible genetic switch and that genes which encode these proteins are clustered on the streptococcal chromosome. We propose that these genes compose a complex regulatory circuit which is controlled by a master gene, the product of the virR locus. We also suggest that this regulatory pathway coordinates the """"""""on off"""""""" expression of these three virulence factors. To test this model the nucleotide sequence of this gene cluster will be completed. The virR gene and its role in coordinating expression and phase variation of these surface protein genes will be investigated. The impact of virR on promoter recognition and transcription of each gene will be examined by quantitating and sizing mRNA transcripts from each gene. Our studies will make use of lacZ gene fusions and insertion mutagenesis to locate and define components of the phasing switch. This project will extend the knowledge of the pathobiology of group A streptococcal infections and could ultimately explain the persistence of streptococci in human populations. Furthermore, this study will yield a wealth of protein sequence information, all proteins which contribute to the pathogenic potential of these bacteria. This information may be useful for the development of a subunit, polyvalent vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI016722-10
Application #
3126790
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1981-09-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Pritchard, K H; Cleary, P P (1996) Differential expression of genes in the vir regulon of Streptococcus pyogenes is controlled by transcription termination. Mol Gen Genet 250:207-13
McLandsborough, L A; Cleary, P P (1995) Insertional inactivation of virR in Streptococcus pyogenes M49 demonstrates that VirR functions as a positive regulator of ScpA, FcRA, OF, and M protein. FEMS Microbiol Lett 128:45-51
Cleary, P P; McLandsborough, L; Pritchard, K H (1995) Differential expression of genes in the vir regulon. Dev Biol Stand 85:145-8
Johansson, P J; Malone, C C; Williams Jr, R C et al. (1994) Streptococcus pyogenes type M12 protein shows selective binding to some human immunoglobulin G3 myeloma proteins. Infect Immun 62:3559-63
LaPenta, D; Rubens, C; Chi, E et al. (1994) Group A streptococci efficiently invade human respiratory epithelial cells. Proc Natl Acad Sci U S A 91:12115-9
La Penta, D; Zhang, X P; Cleary, P P (1994) Streptococcus pyogenes type IIa IgG Fc receptor expression is co-ordinately regulated with M protein and streptococcal C5a peptidase. Mol Microbiol 12:873-9
Cleary, P; Retnoningrum, D (1994) Group A streptococcal immunoglobulin-binding proteins: adhesins, molecular mimicry or sensory proteins? Trends Microbiol 2:131-6
Retnoningrum, D S; Cleary, P P (1994) M12 protein from Streptococcus pyogenes is a receptor for immunoglobulin G3 and human albumin. Infect Immun 62:2387-94
Retnoningrum, D S; Podbielski, A; Cleary, P P (1993) Type M12 protein from Streptococcus pyogenes is a receptor for IgG3. J Immunol 150:2332-40
Chen, C; Bormann, N; Cleary, P P (1993) VirR and Mry are homologous trans-acting regulators of M protein and C5a peptidase expression in group A streptococci. Mol Gen Genet 241:685-93

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