title: Chlamydial protease-like activity factor induces protective immunity against genital chlamydial infection in transgenic mice that express the human HLA-DR4 allele.
abstract: There is no licensed vaccine available against Chlamydia trachomatis, the leading cause of bacterial sexually transmitted disease. We have found that intranasal immunization with recombinant chlamydial protease-like activity factor (CPAF) induces CD4(+) T-cell- and gamma interferon (IFN-gamma)-dependent protective immunity against murine genital chlamydial infection, thus making CPAF a viable vaccine candidate for further characterization. HLA-DR4 is the predominant allele involved in chlamydial antigen presentation to CD4(+) T cells in humans. We used engineered mice that lack endogenous major histocompatibility complex class II (MHC-II) alleles but express a human HLA allele (HLA-DR4 transgenic [tg] mice) to examine primary immune and CPAF-mediated responses against genital Chlamydia muridarum challenge. Upon primary bacterial exposure, HLA-DR4 tg mice developed Chlamydia-specific IFN-gamma and antibody production and resolved the infection within 30 days, similar to challenged conventional C57BL/6 animals. Moreover, C. muridarum-challenged HLA-DR4 tg mice exhibited CPAF-specific antibody and IFN-gamma production. Upon CPAF-plus-interleukin-12 (IL-12) vaccination, HLA-DR4 tg animals exhibited robust CPAF-specific IFN-gamma production and elevated titers of anti-CPAF total antibody and immunoglobulin G2a (IgG2a) and lower titers of IgG2b and IgG1 antibodies. HLA-DR4 tg and C57BL/6 mice vaccinated with CPAF plus IL-12 resolved the primary genital chlamydial infection significantly earlier than mock-immunized animals, whereas similarly vaccinated MHC class II-deficient mice displayed minimal antigen-specific immune responses and failed to resolve the infection even at 30 days postchallenge. Together, these results demonstrate the importance of human HLA-DR4 molecules in the recognition and presentation of CPAF epitopes, leading to the generation of protective antichlamydial immunity and making these mice a valuable model for mapping HLA-DR4-restricted chlamydial epitopes.
authors.affiliation: Department of Biology, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, TX 78249, USA.
authors.forename: Ashlesh K
authors.initials: AK
authors.lastname: Murthy
authors.forename: Yu
authors.initials: Y
authors.lastname: Cong
authors.forename: Cathi
authors.initials: C
authors.lastname: Murphey
authors.forename: M Neal
authors.initials: MN
authors.lastname: Guentzel
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Forsthuber
authors.forename: Guangming
authors.initials: G
authors.lastname: Zhong
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Arulanandam
mesh_terms: D000281:Administration, Intranasal; D000483:Alleles; D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002690:Chlamydia Infections / Q000188:drug therapy / Q000517:prevention & control*; D023502:Chlamydia muridarum; D010450:Endopeptidases / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D005260:Female; D005831:Genital Diseases, Female / Q000188:drug therapy / Q000469:parasitology* / Q000517:prevention & control*; D015804:HLA-DR4 Antigen / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D014611:Vaccination
chemical_list: D015804:HLA-DR4 Antigen; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D007371:Interferon-gamma; D010450:Endopeptidases; C425923:CPA factor