Molecular Studies in Treponema pallidum Evolution: Toward Clarity?

Syphilis is the best known treponemal infection and the disease has captured the attention of well-known physicians and the imaginations of writers and artists. In contrast, the nonvenereal treponemal infections (yaws, bejel, and pinta) have been endemic in remote regions of Africa, Southeast Asia, and South America, and are thus less well-known in western culture. However, these endemic treponematoses were so prevalent that, between 1952 and 1964, the World Health Organization (WHO) undertook a massive eradication campaign in which over 300 million people in Africa, South America, Southeast Asia, the South Pacific islands, and the Middle East were examined and ,50 million were treated with penicillin [1]. It is estimated that the burden of disease was reduced by 95%. In the mid 1980s, the Fogarty International Center and WHO sponsored a series of regional meetings to gather information about the status of the endemic treponematoses [2–4]. Numerous foci of infection were identified in Africa, Asia, and South America, and the recommendation was made to focus new efforts on control, with the goal of elimination. The HIV epidemic intervened and the attention of the global health community was appropriately diverted to AIDS, thus interrupting the momentum for elimination of the treponematoses. Since that time, because of little to no surveillance in many areas, the current magnitude of the diseases is unknown, although foci of yaws and endemic syphilis have periodically been reported. Several countries, including Indonesia and India, have current ongoing yaws control programs. In 2007, the WHO once again committed itself to eliminate yaws (http://www.who.int/ mediacentre/news/notes/2007/np04/en/index.html). Traditionally, the human Treponematoses have been differentiated based upon their mode of transmission (sexual vs. nonvenereal), clinical manifestations, serious sequelae (e.g. central nervous system [CNS] or cardiovascular involvement, congenital infection), and experimental host range (Table 1). In the mid-1900’s, a disagreement raged over whether the etiologic agents of these infections were the same species, with mode of transmission and clinical course defined by culture and climate, or were different species with important biological differences [5,6]. The agents are morphologically identical, and all induce reactivity in the standard serological tests used for syphilis diagnosis. Recent molecular studies have identified genetic signatures that can differentiate the existing strains of Treponema pallidum subspecies pallidum (syphilis), subspecies pertenue (yaws), and subspecies endemicum (bejel) [7], yet the molecular bases for the described differences in transmission and clinical course have not been defined. How definitive are these clinical and epidemiological differences? Syphilis is usually transmitted sexually, but there are many examples in older textbooks of nonsexual transmission via direct contact; examples include digital infection of dentists via contact with oral lesions of syphilis patients, and infection of the nipple in wet nurses via oral lesions in infected infants. In contrast, yaws is generally transmitted by skin-to-skin contact in children, and infectious lesions are typically resolved before sexual debut, thus transmission during sexual activities is not recognized. Thus, mode of transmission appears to be defined by opportunity, rather than biology. There is similar overlap in clinical manifestations. The lesions of yaws are typically described as ‘‘frambesiform’’ (raised ‘‘berry-like’’ lesions compared to the ulcer or maculopapular rash of syphilis) yet there are numerous descriptions in the literature of less dramatic, even macular, yaws lesions in drier climates [8]. Conversely, the condylomata lata of secondary syphilis can be raised and multilobed (‘‘frambesiform’’), and they appear in moist body folds, a common location for the frambesiform lesions of secondary yaws. Although gummatous destruction, particularly of bone and cartilage, is well-recognized in syphilis, yaws, and bejel, only syphilis is said to lead to CNS involvement and congenital infection. However, in a very thoroughly researched review article, Roman and Roman [9] argue eloquently that there is ample evidence for CNS, cardiovascular, and congenital infection in yaws. In that review, Blacklock [10] is quoted as stating that the ‘‘criteria used to differentiate syphilis and yaws were ‘nothing more than the statement of an epidemiological observation.’’’ As an example, the Haiti B strain was originally identified as T. pallidum subsp. pertenue because it was isolated from an 11-year old child with ‘‘typical generalized frambesiform yaws’’ [11], in a epidemiological setting of childhood infection. Yet molecular studies in several labs [12–14] have subsequently demonstrated that the Haiti B strain has molecular signatures consistent with T. pallidum subsp. pallidum. The Madras strain is another such example of a ‘‘yaws’’ isolate that appears in fact to be a pallidum strain based on molecular data. With regard to host range differences, the Haiti B strain was used extensively by Schell et al. [15–17] in their studies of yaws infection in the hamster model. It has been stated that hamsters do not regularly develop clinical manifestations of syphilitic disease [11,17], yet hamsters are readily infected by the Haiti B strain, now considered to be a pallidum strain. Thus the clinical, epidemiological, and host range criteria used to differentiate the agents of the treponematoses are soft.