Syphilis is one of the most fascinating of all infections. Although its origin is still debated, the history of syphilis includes many famous (and infamous) persons, and the disease is featured in art and literature. Syphilis is caused by a corkscrew-shaped bacterium, Treponema pallidum, that was first identified over 100 years ago. It has a miniscule genome, and it lacks many of the common metabolic pathways. It is so fragile that it dies within hours outside of the host, yet it is capable of evading host defences to persist for decades within the host.

Syphilis is known as “the great imitator” because its clinical manifestations, which can range from an ulcer or rash to blindness and insanity, can be mistaken for many other clinical conditions. In contrast, the infection can lie smouldering for many years, without any clinical evidence. After 70 years of use, penicillin continues to be an effective treatment, yet resistance to macrolide antibiotics like azithromycin has erupted in T. pallidum in many regions of the world. Physicians recognise that some persons who are treated for syphilis can be reinfected, sometimes multiple times. At the population level, the incidence of syphilis can wax and wane, often shifting from one population group to another.

How does T. pallidum cause the many manifestations of syphilis and still evade immune clearance? How does macrolide resistance develop and spread? Is there a biological basis for determining which patients can be reinfected or when the incidence of syphilis will decline in a given population? Molecular studies involving the laboratory and the clinic have shed insights into pathogenic mechanisms involved in invasion and dissemination, induction of host responses, and immune evasion by T. pallidum. Molecular epidemiology studies have begun to unravel the movement of T. pallidum strains throughout communities, and to shed light on the appearance of macrolide resistance. Our evolving knowledge about these issues will be discussed in the context of the natural history of syphilis.