Decipher Syphilis: Skin Immunity Against Treponema pallidum

Syphilis is a resurgent sexually transmitted infection caused by corkscrew-shaped bacteria (Treponema pallidum). These bacteria typically enter the body through the skin or mucosal surfaces, forming sores before spreading and causing various symptoms such as rashes. There is currently no vaccine available, treatment options are limited, and infection rates continue to rise, making new prevention and therapeutic strategies an urgent priority. This project investigates what happens in the skin during syphilis infection. The skin is both the entry point for the bacteria and the first line of defense. We hypothesize that specialized skin-resident immune cells play a critical early role in controlling infection, but that their responses are insufficient and hence require strengthening. By identifying these cells and decoding their activity, we aim to develop targeted strategies to block infection before it spreads. Our approach includes three major components: Firstly, we will analyze skin biopsies from syphilis patients to determine which immune cells are present and which genes are active during infection. In parallel, we will infect healthy human skin samples with live bacteria and track how immune responses unfold in real time in a controlled laboratory setting. Lastly, we will assess how bacteria interact with both innate and adaptive immune cells to understand what is needed to eliminate bacteria early, and generate lasting immune memory. Historically, research on syphilis has been hampered by the difficulty of culturing T. pallidum outside animals. A newly developed, animal-free culture method now makes it possible to grow the bacteria and perform infection studies directly in human skin models. By combining this approach with state-of-the- art single-cell technologies, we will observe how bacteria and immune cells behave in biologically relevant human tissue. This project brings together several cutting-edge approaches: animal-free bacterial culture, physiologically relevant human tissue models, and single-cell analysis paired with spatial imaging. Together, these tools will provide the most detailed picture to date of how skin immune cells respond to syphilis infection. The insights gained may reveal new targets for prevention, therapy, and ultimately vaccine development.