The goal of this proposal is to identify and characterize continuous neutralizing epitopes of the major outer membrane protein (MOMP) of Chlamydia trachomatis. This organism is the leading cause of preventable blindness and sexually transmitted diseases, therefore protection through an effective vaccine would be desirable. Vaccine trials in the past which have employed the whole organism for immunization have failed, partly due to hypersensitivity reactions. An alternate approach to immunization is to engineer a subunit vaccine where only epitopes that elicit a protective host response are included. To identify such key epitopes MOMP was chosen as the focus of this investigation since it is surface exposed, has been shown to elicit neutralizing antibodies and DNA sequence data is available and thus the derived amino add sequence. More specifically variable domain (VD) IV will be the main focus of this proposal since antibodies that neutralize the B-,B-related and C-related complexes have been mapped to this region. However, MAbs that have mapped to this region fail to neutralize members of the C-complex Therefore, in addition to VD IV, VD I and VD 11 will be examined with C-complex serovars in order to be more successful in identifying continuous neutralizing epitopes that are broadly reactive and neutralize these members of the species. Peptides representing VD IV from serovars L2 and E and VD I, II and IV from serovar C will be used to immunize mice. Both the polyclonal sera as well as MAbs resulting from the immunizations will be examined for their ability to neutralize C. trachomatis. This will be accomplished by performing in vitro neutralization assays. In addition, the Geysen technique will be used to map recognition sites by ELISA using overlapping hexameric peptides to the VD used in the immunizations. The functional, i.e., neutralizable, site will be determined by competition experiments in which the neutralizing antibodies will be competed for by viable C. trachomatis and peptides to the region of interest. The spectrum of serovars neutralized by the antibodies will be established as well as the ability of the antibodies to act in an additive or synergistic manner. Mice will be immunized with peptide conjugates or passively immunized with MAbs that are identified as broadly neutralizing in terms of serovars. These animals will then be challenged with C. trachomatis in both a systemic as well as a mucosa] model of infection. In addition, studies aimed at determining the mechanism(s) of inhibition of the broad neutralizing MAbs will be performed. The work proposed in this investigation will provide structure-function information about a key structural protein of this organism and will be useful in the future design of vaccines to control the spread and growth of this important human pathogen.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacteriology and Mycology Subcommittee 2 (BM)
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University of California Irvine
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United States
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Pal, S; Theodor, I; Peterson, E M et al. (2001) Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein can elicit a protective immune response against a genital challenge. Infect Immun 69:6240-7
Pal, S; Peterson, E M; de La Maza, L M (2000) Role of Nramp1 deletion in Chlamydia infection in mice. Infect Immun 68:4831-3
Pal, S; Barnhart, K M; Wei, Q et al. (1999) Vaccination of mice with DNA plasmids coding for the Chlamydia trachomatis major outer membrane protein elicits an immune response but fails to protect against a genital challenge. Vaccine 17:459-65
Peterson, E M; You, J Z; Motin, V et al. (1999) Intranasal immunization with Chlamydia trachomatis, serovar E, protects from a subsequent vaginal challenge with the homologous serovar. Vaccine 17:2901-7
Pal, S; Rangel, J; Peterson, E M et al. (1999) Immunogenic and protective ability of the two developmental forms of Chlamydiae in a mouse model of infertility. Vaccine 18:752-61
Motin, V L; de la Maza, L M; Peterson, E M (1999) Immunization with a peptide corresponding to chlamydial heat shock protein 60 increases the humoral immune response in C3H mice to a peptide representing variable domain 4 of the major outer membrane protein of Chlamydia trachomatis. Clin Diagn Lab Immunol 6:356-63
Pal, S; Peterson, E M; De La Maza, L M (1999) A murine model for the study of Chlamydia trachomatis genital infections during pregnancy. Infect Immun 67:2607-10
Peterson, E M; de la Maza, L M; Brade, L et al. (1998) Characterization of a neutralizing monoclonal antibody directed at the lipopolysaccharide of Chlamydia pneumoniae. Infect Immun 66:3848-55
Pal, S; Hui, W; Peterson, E M et al. (1998) Factors influencing the induction of infertility in a mouse model of Chlamydia trachomatis ascending genital tract infection. J Med Microbiol 47:599-605
Peterson, E M; Cheng, X; Motin, V L et al. (1997) Effect of immunoglobulin G isotype on the infectivity of Chlamydia trachomatis in a mouse model of intravaginal infection. Infect Immun 65:2693-9

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