TprK Variation and Syphilis Pathogenesis

Abstract

Treponema pallidum subsp. pallidum is the etiologic agent of syphilis, a multistage disease that poses a global health problem. Despite the availability of curative therapy and ongoing public health efforts to eradicate syphilis, the disease is re-emerging in developed countries and remains prevalent in other locations. Calculating the basic reproductive number (Ro) of syphilis allows for the estimation of the number of people infected by a single infectious person. Ro is proportional to the duration of infectiousness, efficiency of transmission, and the number of new susceptible contacts. An infectious disease is expected to increase prevalence in a population when Ro>1, and will die out if Ro< 1. It is known that antibodies directed to exposed surface antigens are critical for opsonophagocytosis and clearance of this pathogen from lesions. TprK is a T. pallidum antigen that undergoes antigenic variation during infection. Evidence shows that antibodies are directed to the variable regions of the protein and TprK sequence changes abrogate antibody binding, thus allowing immune escape. This dissertation describes TprK`s effect on two of the three parameters used to calculate Ro. The first is the role of TprK variation in duration of infectiousness, exemplified by the association found between TprK variants and secondary lesions. Length of the infectious period is increased by facilitating development of the second stage of syphilis in the face of developing opsonic antibody to TprK. The second component of Ro impacted by TprK variation is the number of new susceptible contacts an infected individual encounters. TprK variation contributes to T. pallidum's ability to reinfect or superinfect individuals that have been previously exposed by altering opsonic antibody epitopes such that newly infecting treponemes escape the established immune response. In summary, antigenic variation of TprK is associated with the ability of the spirochete to re-infect previously exposed individuals, and increase the duration of infectiousness by facilitating persistence into the second stage of syphilis. Antigenic variation of the outer membrane protein, TprK, accounts for a larger estimated Ro value for syphilis, and thus may be associated with its centuries of success as a devastating disease.