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Infection and Immunity, December 2006, p. 6722-6729, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01119-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Chlamydial Protease-Like Activity Factor Induces Protective Immunity against Genital Chlamydial Infection in Transgenic Mice That Express the Human HLA-DR4 Allele{triangledown}

Ashlesh K. Murthy,1,{dagger} Yu Cong,1,{dagger} Cathi Murphey,1 M. Neal Guentzel,1 Thomas G. Forsthuber,1 Guangming Zhong,2 and Bernard P. Arulanandam1*

Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249,1 Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, Texas 782292

Received 17 July 2006/ Returned for modification 12 September 2006/ Accepted 22 September 2006

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.

* Corresponding author. Mailing address: Department of Biology, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, TX 78249. Phone: (210) 458-5492. Fax: (210) 458-5523. E-mail: Bernard.arulanandam{at}utsa.edu.

{triangledown} Published ahead of print on 2 October 2006.

Editor: A. D. O'Brien

{dagger} A.K.M. and Y.C. contributed equally to the manuscript.

Infection and Immunity, December 2006, p. 6722-6729, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01119-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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