Syphilis Immunology and Biology to Improve Clinical Management and Vaccine Design

About This Grant

PROJECT ABSTRACT The proposed study will help substantially advance understanding of the immunology, biology, and detection of syphilis, through the study of newly identified cases in Lima, Peru, where syphilis is hyper-endemic. Syphilis remains a serious disease with significant adverse clinical outcomes. Despite over 100 years of research in the biology of Treponema pallidum sub. pallidum, the bacterial pathogen that causes syphilis, the use of modern methods to study this infection is just beginning, with our team spearheading some of this work. Our study builds on the research infrastructure and capacity created through two previously NIH-funded studies, the “Picasso Study” (NIH/NIAID R01AI09972) and “Picasso 2” (NIH/NIAID R01AI139265) as well as an SBIR grant (R43AI149804). In this proposal, investigators from USC, UPCH, UW, and Antigen Discovery will work together to accomplish the proposed three aims and fill critical gaps in the understanding of syphilis. Aim 1: Clinical cohort and epidemiology — Hypothesizing that those with a first versus repeat syphilis infection will demonstrate different immunological profiles, we will conduct a prospective study of incident syphilis cases, comparing those with and without a history of prior syphilis infection. We will a) recruit, treat, and follow 50 individuals with incident syphilis without prior infection and 100 individuals with repeat syphilis infection. We will compare individuals with de novo versus repeat infection with two outcomes: 1.the proportion with clinical manifestations of syphilis at diagnosis and 2. rates of re-infection during follow-up. Aim 2: Immunological — Hypothesizing that the clinical manifestations and immunologic responses (antibody responses and T cell activation) will differ between individuals with repeat infection versus de novo incident syphilis infection (active versus treated infection), we will investigate antigens associated with reinfection, identify TP proteins that activate a CD4 T cell response, and document the T cell receptor response to infection and treatment. Aim 3: Transcriptomics — we will analyze the host transcriptome to identify diagnostic signatures for syphilis. Assays for syphilis remain limited in their ability to differentiate between active and resolved infection. In this study, RNA- seq data from whole blood collected pre and post treatment will be used to identify transcription pathways involved in functional immunity to syphilis. Building on our years of ongoing collaborative work in syphilis pathogeneses and diagnostics, this proposal will focus on new areas of syphilis immunology to inform vaccine discovery and novel diagnostic test development.