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Syphilis, a multistage, sexually transmitted infection is caused by the highly invasive and immuno-evasive spirochete Treponema pallidum subsp. pallidum (T. pallidum) (1, 2). Syphilis remains a major global public health threat causing approximately seven million new infections annually (3, 4). Although the efficacy of penicillin therapy for syphilis remains undiminished after more than seven decades of use (1, 5), the explosive resurgence of the disease in the new millennium has fueled a sense of urgency for a vaccine with global efficacy (6, 7) and the World Health Organization has set ambitious targets to reduce the incidence of syphilis by 90% by 2030. T. pallidum is an extracellular pathogen (8, 9), with a low abundance of surface proteins, known as outer membrane proteins (OMPs). OMPs form b-barrels with large extracellular loops (ECLs) that extend from the surface of the organism into the extracellular space. These ECLs are acceptable to antibodies produced during infection with the spirochete. It is generally believed that these antibodies are critical for spirochete clearance and subsequent containment of the pathogen (10, 11). Ex vivo studies have demonstrated that antibodies in human syphilitic serum promote uptake and degradation of T. pallidum by professional phagocytes, such as macrophages (12, 13). The exact target(s) of the antibodies present in human syphilitic serum that lead to uptake of the spirochete has yet to be determined. Strategies for vaccine design often are predicated on the ';learning from nature'; paradigm that immunization should mimic the protective response evoked by the infecting pathogen (14). Extrapolating to syphilis, a successful vaccine should elicit antibodies against targets on the T. pallidum surface, with opsonic activity serving as an ex vivo correlate of protective immunity (10, 11). Having knowledge about the antigenic response to T. pallidum OMPs, more specifically ECLs, of a given serum sample or ECL-specific monoclonal antibodies in the ex vivo human macrophage system may give rise to novel vaccine candidate against an organism that has been plaguing mankind for centuries Hypotheses or Research Question, Aims and Objectives: Hypothesis/Question: To address the above information gaps, this study seeks to illuminate the key antibodies present in human syphilitic serum that lead to the clearance of spirochetal infection. Aims / objectives: Confirm samples of syphilitic serum evaluated have opsonic potential to pathogenic spirochetes. Use an ex vivo human macrophage system to investigate how human syphilitic serum and/or T. pallidum-specific monoclonal antibodies influence innate immune responses. Study how the antibody-opsonized spirochetes shape innate responses imminent adaptive responses in syphilis.
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