SUMMARY Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subsp. pallidum. Clinical manifestations separate the disease into stages; late stages of disease are now uncommon compared to the preantibiotic era. T. pallidum has an unusually small genome and lacks genes that encode many metabolic functions and classical virulence factors. The organism is extremely sensitive to environmental conditions and has not been continuously cultivated in vitro. Nonetheless, T. pallidum is highly infectious and survives for decades in the untreated host. Early syphilis lesions result from the host's immune response to the treponemes. Bacterial clearance and resolution of early lesions results from a delayed hypersensitivity response, although some organisms escape to cause persistent infection. One factor contributing to T. pallidum's chronicity is the paucity of integral outer membrane proteins, rendering intact organisms virtually invisible to the immune system. Antigenic variation of TprK, a putative surface-exposed protein, is likely to contribute to immune evasion. T. pallidum remains exquisitely sensitive to penicillin, but macrolide resistance has recently been identified in a number of geographic regions. The development of a syphilis vaccine, thus far elusive, would have a significant positive impact on global health.

Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.

The complex relationships between infectious organisms and their hosts often reflect the continuing struggle of the pathogen to proliferate and spread to new hosts, and the need of the infected individual to control and potentially eradicate the infecting population. In the case of mammals and the pathogens that infect them, a veritable “arms race” has ensued. A highly adapted immune system has evolved to control the proliferation of infectious organisms and the pathogens have developed correspondingly complex genetic systems to evade this immune response. Here, we review how bacterial, protozoan and fungal pathogens from distant evolutionary lineages have evolved surprisingly similar mechanisms of antigenic variation to avoid eradication by the host immune system and thus maintain persistent infections, thereby ensuring their transmission to new hosts.

Central nervous system invasion by T. pallidum is common in early syphilis, and is apparently independent of HIV infection. Examination of the CSF may be beneficial in patients with early syphilis, and therapy should be guided by knowledge of central nervous system involvement. Conventional benzathine penicillin G therapy may have reduced efficacy in patients with early syphilis who are also infected with HIV.