University of Washington (UW) Sexually Transmitted Infections (STI) Cooperative Research Center (CRC) - Syphilis Vaccine to Protect against Local and Disseminated T. pallidum Infection

点击翻译按钮获取中文摘要

PROJECT SUMMARY Syphilis has been a scourge on humanity for hundreds of years. It has been impossible to eradicate due to biological and societal barriers. Despite curative therapy and multiple public health campaigns to eliminate syphilis in the US, the incidence is rising in diverse groups: men who have sex with men, women, and children. An effective syphilis vaccine will be a key tool in the eradication of this disease. Prior efforts to create a protective syphilis vaccine focused on raising antibodies against rare outer membrane proteins to facilitate antibody mediated opsonophagocytosis of Treponema pallidum (Tp) in infectious lesions. These vaccines only generate partial protection in the rabbit model and have not advanced to human trials. Notably, these candidate antigens did not specifically target T cell responses. We believe that better understanding of T cell specificity and phenotype will provide insights into novel strategies to design an effective syphilis vaccine. For example, the inclusion of immunodominant T cell antigens in a subunit vaccine can provide CD4 T cell help to B cells to produce opsonic antibodies. At this time, there are no reported human Tp T cell antigens validated to the epitope level. Aim 1 focuses on identifying immunodominant CD4 T cell antigens. We will use rare cell enrichment to measure, sort and then expand Tp-specific CD4 T cells. We will expand our extant panel of recombinant proteins to probe CD4 T cells, determine which Tp protein antigens are recognized, and follow up antigen-level hits to the peptide epitope level. Less is known about the CD8 response during syphilis. While T. pallidum is canonically extracellular and as such not expected to elicit a classic peptide-specific CD8 T cell response, we know that there are abundant CD8-expressing cells within active syphilis lesions. We don't know if they are responding to Tp peptide epitopes, or if they are classic or innate-spectrum lymphocytes. Aim 2 focuses on better understanding the CD8 response. Multicolor immunohistochemistry will determine if these CD8-expressing cells are classic T cells with hypervariable TCRs, or cells such as NK, NKT, MAIT, or gamma-delta T cells. Their phenotype will guide future studies towards determination of the Tp-associated molecules recognized by these cells. Overall, knowledge of Tp T cell antigens will significantly improve our ability to design the next- generation candidate vaccines against syphilis.