The natural history of untreated syphilis includes distinct primary and secondary stages of disease typified by a chancre at the site of infection and a disseminated rash, respectively. These lesions spontaneously resolve, followed by a period of asymptomatic latency that lasts for the remainder Apoptosis Compound Library price of their lifetimes in most persons. In the pre-antibiotic era, approximately 30% of untreated infected individuals developed tertiary syphilis 10–50 years after initial infection, with the possibility of life-threatening sequelae [36]. The course of untreated infection has provided insight into the critical pathogenic mechanisms utilized by

T. pallidum to establish and maintain a successful infection. Two key mechanisms that are essential for T. pallidum survival are (1) its high invasive capability and (2) its impressive capacity to evade the immune response and persist for extended periods of time. The highly invasive nature of T. pallidum is most dramatically illustrated by the ability of the pathogen to cross the placental barrier to cause CS and by the fact that at least 40% of patients with

early syphilis have CNS invasion [37]. However, dissemination of infection is also exemplified by the widespread secondary rash, the sometimes symptomatic involvement of liver and kidneys, and ocular involvement. Within hours of infection in experimental animals, the highly motile T. pallidum disseminates widely via

the bloodstream and lymphatics [38] and [39], PLX4032 order and in vitro studies have shown T. pallidum can penetrate intact membranes and endothelial cell monolayers [40] and [41]. Invasion of tissues can result only following attachment of T. pallidum to cells (e.g. endothelial cells that comprise capillary walls). Several proteins that are active in attachment to host cells, via extracellular matrix bridges, include Tp0136 [42], Tp0155, Tp0483 [43] and Tp0751/pallilysin [44], [45], [46], [47] and [48]. The invasive capability of T. pallidum is crucial to the development of the many clinical manifestations of syphilis, and elimination of this capability should be a central target of a syphilis aminophylline vaccine to prevent transmission of infectious syphilis, establishment of CS, and progression of disease within an infected individual. Primary and secondary syphilis lesions are infiltrated primarily by T lymphocytes, followed by macrophages. The vast majority of treponemes are cleared, with lesion resolution, shortly after macrophage infiltration [49], [50], [51] and [52]. Detailed examination of the various steps involved in clearance has revealed there is a Th1-type cellular infiltration in which both CD4+ and CD8+ T lymphocytes produce interferon-gamma (IFN-γ). This cytokine attracts and activates macrophages, which are then able to ingest and kill antibody-opsonized treponemes [49] and [53].