): The long-term objective of the proposed research is to define the molecular basis for the tissue specificity of group A beta-hemolytic streptococcal (GABHS) infection, and to define the role of emm gene products in pathogenesis. Although GABHS can thrive in almost any bodily tissue, it is the nasopharynx and impetigo lesion that serve as the primary sites of infection and principal reservoirs for transmission. The existence of distinct populations of throat and skin strains have long been suspected, but never proven on a molecular level. Recent studies have uncovered an organization that links different GABHS diseases (pharyngitis, impetigo, rheumatic fever) to the structure and function of emm genes, emm gene products, and emm-linked traits. The emm genes encode a diverse family of surface proteins, many of which are key virulence factors. The genetic distinction between pharyngeal and impetigo strains provides focus for addressing the molecular basis for the tissue-specificity of GABHS infection. Using genetically altered pharyngeal- and impetigo-derived GABHS, the contribution of emm genes and co-inherited traits to the tissue- specificity of GABHS infection will be established (Aim 1). Experimental models for pharyngeal infection (mouse) and impetigo (hamster) will be employed. If an emm gene product contributes to tissue-specific infectivity, the functional domain within M protein will be indentified by testing the relative infectivity of organisms that harbor mutated emm genes. If non- emm genes have a tissue-specific role, the contribution of two closely- linked genes (mga and scpA) will be explored (Aim 2). The role of the multiple emm gene products of impetigo isolates as targets of protective antibody and as mediators of the antiphagocytic effect will be assessed (Aim 3). This knowledge is crucial to an understanding of autoimmune diseases initiated by a tissue-restricted GABHS infection, e.g., rheumatic fever, and for the development of a vaccine that is both broad- based, and of high efficacy. If emm gene products define, at least in part, the tissue specificity of infection, than the horizontal transfer of emm genes that occurs between different GABHS strains may be an important mechanism for the emergence of new clones having unique pathogenic qualities and also, may lead to a change in the principal reservoir for transmission of that clone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028944-08
Application #
2886634
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Rubin, Fran A
Project Start
1990-05-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kalia, Awdhesh; Bessen, Debra E (2004) Natural selection and evolution of streptococcal virulence genes involved in tissue-specific adaptations. J Bacteriol 186:110-21
Kalia, Awdhesh; Bessen, Debra E (2003) Presence of streptococcal pyrogenic exotoxin A and C genes in human isolates of group G streptococci. FEMS Microbiol Lett 219:291-5
Bessen, Debra E; Kalia, Awdhesh (2002) Genomic localization of a T serotype locus to a recombinatorial zone encoding extracellular matrix-binding proteins in Streptococcus pyogenes. Infect Immun 70:1159-67
Svensson, Mikael D; Sjobring, Ulf; Luo, Feng et al. (2002) Roles of the plasminogen activator streptokinase and the plasminogen-associated M protein in an experimental model for streptococcal impetigo. Microbiology 148:3933-45
Kalia, Awdhesh; Spratt, Brian G; Enright, Mark C et al. (2002) Influence of recombination and niche separation on the population genetic structure of the pathogen Streptococcus pyogenes. Infect Immun 70:1971-83
Kalia, A; Enright, M C; Spratt, B G et al. (2001) Directional gene movement from human-pathogenic to commensal-like streptococci. Infect Immun 69:4858-69
Enright, M C; Spratt, B G; Kalia, A et al. (2001) Multilocus sequence typing of Streptococcus pyogenes and the relationships between emm type and clone. Infect Immun 69:2416-27
Scaramuzzino, D A; McNiff, J M; Bessen, D E (2000) Humanized in vivo model for streptococcal impetigo. Infect Immun 68:2880-7
Bessen, D E; Carapetis, J R; Beall, B et al. (2000) Contrasting molecular epidemiology of group A streptococci causing tropical and nontropical infections of the skin and throat. J Infect Dis 182:1109-16
Svensson, M D; Scaramuzzino, D A; Sjobring, U et al. (2000) Role for a secreted cysteine proteinase in the establishment of host tissue tropism by group A streptococci. Mol Microbiol 38:242-53

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