by Julia Messina-Pacheco and Lara Montaruli
Within the past three decades, an important reemergence of Treponema pallidum infections has been observed worldwide. This infection manifests itself as syphilis and other treponemal diseases such as bejel, pinta and yaws. Most often acquired through close sexual contact, this helically coiled bacterium belongs to the spirochete phylum, which is distinguished by a double membrane. Despite T. pallidum being one of the first successful antibiotic-treated infections, discussion still surrounds the most effective treatment, mainly due to the inability to culture it in vitro and thus study its antimicrobial susceptibility.
Syphilis is caused by T. pallidum subspecies pallidum, and is divided into four stages of disease progression (primary, secondary, latent and tertiary). The primary stage symptoms are sores at the site of infection, generally around the genitals, anus or mouth and are usually firm, round and painless. Secondary syphilis causes skin rashes, swollen lymph nodes and fever. Once the latent stage is reached, there are no signs or symptoms, as the infection lays ‘dormant’ for multiple years. If left untreated, the disease progresses to the tertiary stage wherein inflammation, apathy, seizures, general paralysis with dementia, and aneurysm formation occur. T. pallidum is generally transmitted through sexual contact, primarily in homosexual men (see Figure 1). It can also be transmitted by transplacental passage during the later stages of pregnancy, giving rise to congenital syphilis. It is highly transmissible as approximately 30% to 60% of those exposed to primary or secondary syphilis will become infected. However, chances of transmission during sex are reduced through the use of condoms to protect the infected area or site of potential exposure.
Figure 1: Number of early syphilis cases by sexual transmission routes between 1992-2008 in Norway. The primary route of transmission overall is by men having sex with men. Source: Biomed Central, BMC Infectious Diseases, Jakopanec et al. (2010) https://doi.org/10.1186/1471-2334-10-105)
Syphilis rates steadily decreased with the introduction of penicillin in 1947. However, it was not until the 1980s when the trend reversed in concurrence with increased use of intravenous drugs, the exchange of sex for drugs, anonymous sex, and people with multiple sexual partners, reaching its peak of 53.8 cases per 100,000 population in 1990. Still, syphilis rates continue to increase, for example, in the United States, the number of confirmed primary and secondary syphilis cases almost doubled, jumping from 8 724 to 16 663 between the years 2005 and 2013.
The disease primarily affects individuals between 15 and 40 years of age as there is a direct correlation between incidence of T. pallidum infection and increased sexual activity. Furthermore, there is a noticeable difference in syphilis rates between men and women: males affected with primary and secondary syphilis outweigh females 10 to 1. On an international level, syphilis is distributed worldwide but remains prevalent in developing countries with rates being highest in the Western Pacific region and Southeast Asia.
Although T. pallidum may not exhibit the ‘classical’ virulence factors produced by most pathogens, it successfully attaches to, disseminates through and invades host tissues. These bacteria attach to a variety of host cell types by interacting with different host membrane components. In addition, its spiral shape (see Figure 2) allows it to enter through breaches in the skin and easily swim through gel-like substances, such as mucous membranes, to gain access to host blood and lymph systems. Thus, it propels itself by rotating in a corkscrew-like motion. Unlike most motile bacteria whose flagella are extracellular, in this case, the flagella is located in the space between the cytoplasmic and outer membranes, hidden from the host defenses. One of the major components of the host immune system is the generation of specific proteins, called antibodies, that recognize invading pathogens by binding to molecules on their surface. These immunogenic surface molecules are called ‘antigens’ and can be proteins, carbohydrates, or lipids. As such, the flagella of motile bacteria are composed of protein subunits called flagellin, which constitute a group of proteins called the H antigens. The outer membrane thus forms a barrier between the host defenses and T. pallidum‘s flagellum, preventing the binding of host antibodies to H antigens. In addition, T. pallidum is referred to as the ‘stealth pathogen’ due to the sparsity of immunogenic molecules presented on its outer surface, allowing it to avoid triggering an immune response. However, the few proteins that are presented on its surface are highly variable between individual bacteria of the same species. Thus, pathogens such as T. pallidum that can switch the molecular composition of their surface antigens are said to undergo ‘antigenic variation’. This makes it very difficult for the host to identify the bacterial molecules and subsequently raise an appropriate immune response. All in all, this bacterial pathogen effectively bypasses recognition by the host immune system by altering its surface components and by hiding its flagellum, two potential sources of antigenic molecules.
Figure 2: A photomicrograph showing the spiral, corkscrew-like shape of Treponema pallidum. The periplasmic flagella allows for the dissemination of the pathogen through host tissues and viscous substances, while preventing recognition by the host defenses. Source: Public Health Image Library, Center for Disease Control, Susan Lindsley (1972).
To date, there is no vaccine available against T. pallidum due to the sparsity and variability of its surface antigens. Thus, in order to successfully treat syphilis, early detection is crucial and followed by antibiotic treatment of syphilis-infected individuals and their partners. Both the CDC and WHO recommend a 10-day course of penicillin for early syphilis, with longer courses of treatment for those with late syphilis. In fact, penicillin is the only antibiotic shown to be effective in treating syphilis in pregnant women, as macrolides do not cross the placental barrier. However, individuals with penicillin allergies should be given doxycycline (cannot be taken during pregnancy) or ceftriaxone. The commonly used antibiotic azithromycin is not recommended, as resistance has emerged in strains of T. pallidum.
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