Treponema pallidum
A Microbial Biorealm page on the genus Treponema pallidum
Classification
Higher order taxa
Eubacteria; Spirochaetes; Spirochaetes; Spirochaetales; Spirochaetaceae; Treponema
Species
Treponema pallidum, T. pertenue, T. endemicum
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NCBI: Taxonomy |
Description and significance
Treponema pallidum is a Gram-negative bacteria which is spiral in shape. It is an obligate internal parasite which causes syphilis, a chronic human disease. Syphilis is a sexually transmitted disease but transmission can also occur between mother and child in utero; this is called congenital syphilis. Syphilis was first discovered in Europe near the end of the fifteenth century. The virulent strain of T. pallidum was first isolated 1912 from a neurosyphilitic patient by Hideyo Noguchi, a Japanese bacteriologist. Although for the past decades treatment has been available, syphilis remains a health problem throughout the world. (1) The WHO (world health organization) “estimates that 12 million new cases of syphilis occur each year.” (2) This is a major problem in developing countries where prenatal testing and antibiotics are not available. In such cases syphilis can be passed from mother to unborn child. In a recent study, congenital syphilis was reported as the cause of 50% of all stillbirths in Tanzania. (3) Another major complication of syphilis is its ability to increase the likelihood of transmission of HIV. (4)
T. pallidum is an important organism because of its ability to cause disease in humans and in efforts to better understand it, its genome was sequenced in July of 1998. T. pallidum cannot be cultured in the lab and therefore cannot be investigated using conventional lab techniques. By sequencing its genome, scientists are able to better understand T. pallidum, however many things remain a mystery, most notably what exactly is the virulence factor of this bacteria. (5)
Genome structure
The complete genome for T. pallidum was sequenced in July of 1998. The genome was sequenced using “the whole genome random sequencing method”. The genome consists of a single double stranded circular DNA chromosome 1,138,006 base pairs long. It contains approximately 1,090 genes which encode approximately 1,041 proteins. These open reading frames account for 92.9% of the genomic DNA. 55% of genes were assigned defined roles and 17% were categorized based on similarities to other organisms. The main organism used for comparison was Borrelia burgdorferi which is another pathogenic spirochete which causes lyme disease. 28% of genes were considered novel (unique to T. pallidum) and placed in a separate category. The average size of encoded proteins was estimated to range from 3235 to 172,869 daltons. (5)
Cell structure and metabolism
T. pallidum is a Gram-negative bacteria consisting of an inner membrane, a thin peptidoglycan cell wall, and an outer membrane. It is very small in size with a length that ranges from 6 to 20 um and a diameter range of 18-20 um. T. pallidum is a member of the spirochete family which are characterized by their distinct helical shape. Probably the most interesting property of T. pallidum’s structure is the endoflagella found in the periplasmic space between its two membranes. These organelles give T. pallidum its distinctive corkscrew motility. (1)
T. pallidum is a chemoheterotroph which encodes few proteins; therefore, it has very limited metabolic capacity. T. pallidum is also microaerophilic, meaning that it requires a very low concentration of oxygen. (6) It doesn’t have the ability to code for many enzymes and as a consequence, it is unable to “synthesize fatty acids, nucleotides, enzyme cofactors and most amino acids”. Although it contains the enzymes necessary for glycolosis, it lacks those which are required for the citric acid cycle as well as those needed for oxidative phosphorylation; therefore it obtains all of its energy through glycolysis. T. pallidum imports molecules via 18 ATP-binding cassettes which are each specific for certain carbohydrates, amino acids or cofactors. DNA replication, transcription, translation, and repair mechanisms for T. pallidum are intact. Another consequence of T. pallidum’s small coding capacity is that it must rely heavily on its host for nutrients making it extremely hard to culture in the lab. (7)
Ecology
T. pallidum is an obligate internal parasite, meaning that it requires a mammalian host for survival. In the absence of mammalian cells, T. pallidum will be killed by the absence of nutrients, exposure to oxygen and heat. (1) T. pallidum causes the human disease syphilis. Since T. pallidum cannot be grown in culture, animal models are needed to study syphilis. Although mice and monkeys can be used, rabbits are the animal model almost exclusively studied in the lab. Rabbits are used because unlike monkeys they are inexpensive and unlike mice, rabbits develop the signs and symptoms of human primary and secondary syphilis. (8)
T. pallidum initially infects the epithelial cells of the genitals during sexual intercourse. From this initial infection site, T. pallidum goes on to infect almost any organ or tissue in the body. (1) A study done using rabbits detected the presence of T. pallidum in the “lymph nodes, brain, and aqueous humor, and in the CSF” after only 18 hours post infection. (9) Another study showed that T. pallidum was then able to travel from the CSF to the eye. (10) T. pallidum has also been found in the blood and liver of infected rabbits. (9)
Pathology
T. pallidum is the causative agent of syphilis, a chronic infectious human disease transmitted between individuals via sexual intercourse or from mother to child in utero. T. pallidum’s virulence factor is still unknown. Untreated syphilis progresses in a series of distinct stages (primary, secondary, latent, and tertiary.) “Infection is initiated when T. pallidum penetrates dermal microabrasions or intact mucous membranes” resulting in primary syphilis. Primary syphilis usually presents itself as a single chancre at the site of infection. Secondary syphilis occurs approximately 3 months after infection and presents itself with a variety of symptoms, most notably lesions of the skin and mucous membranes. These include a rash commonly on the palms of the hands, soles of the feet, face, and scalp. The breakdown of mucous membranes appears as patches on lips, inside the mouth, vulva, and vagina. Infected individuals may also experience fever, loss of appetite and weight loss during this stage. After several months, secondary symptoms will disappear; this is called the latent phase. Even though the infected individual is no longer showing symptoms, testing confirms that T. pallidum is still present. Transmission at this stage via sexual contact is rare. If untreated, latent phase may progress to tertiary phase. Tertiary syphilis doesn’t manifest until years after initial infection (if it does at all) and can affect many different areas of the body. Tertiary syphilis can cause destructive lesions on skin and bones which are usually benign. The more deadly manifestations of late syphilis affect the cardiovascular system (especially the aorta) and the central nervous system causing infected individuals to experience insomnia and changes in personality. (1)
Application to Biotechnology
T. pallidum cannot be cultured in lab which leads to many hurdles for syphilis researchers. The main reason T. pallidum cannot be cultured is because it cannot survive outside of mammalian cells. The current method for studying T. pallidum is by infecting the testes of rabbits with the bacteria. This makes any biotechnology applications at the moment impossible because not only are many enzymes produced functions unknown but also because these enzymes are hard to purify. There is a big push right now for researchers to come up with the right conditions to culture T. pallidum as well as other obligate internal parasites. (1)
Current Research
For over 60 years, penicillin has been the drug of choice for treatment of syphilis. Even though there has been almost no sign of antibiotic resistance by T. pallidum, in the 1990’s scientists developed an alternative to penicillin therapy. The new drug, Azithromycin, is an attractive choice because it can be given orally as opposed to penicillin which must be delivered intramuscularly in large amounts. Recently, a group of scientists discovered macrolide resistance in T. pallidum to Azithromycin among their population of study (United States and Ireland). The acquired resistance was due to a mutation in the 23S rRNA gene of T. pallidum. Using a sample size of 114 individuals from 4 different areas (San Francisco, Dublin, Seattle and Baltimore) they identified the mutation “in 15 of 17 samples (88 percent) from Dublin, 12 of 55 samples (22 percent) from San Francisco, 3 of 23 samples (13 percent) from Seattle, and 2 of 19 samples (11 percent) from Baltimore.” In San Francisco they identified the mutation in “1 of 25 (4 percent) from the period 1999 through 2002, as compared with 11 of 30 (37 percent) from 2003.” Based on their data, the authors suggest that penicillin therapy should be given over Azithromycin therapy, but suggest that patients that are given Azithromycin be extensively followed over their course of treatment. (11)
The current method for detecting syphilis is based on recognition of its signs and symptoms followed by blood tests which lack sensitivity and require fresh serum. The goal of this study was to develop a sensitive assay to directly test for syphilis. They were able to develop a TaqMan real-time PCR assay that was able to detect T. pallidum from “swabs and biopsy specimens from genital and mucosal ulcers, placental specimens, and cerebrospinal fluid. “ Further research is required to confirm the accuracy of this new assay. This will be done by comparing results of this new method against other currently used test for syphilis. (12)
The main hurdle in studying T. pallidum is its inability to be cultured. Metagrowth is a web database containing information that will be vital for developing culture conditions for obligate parasitic bacteria. The information listed in the database is collected from “various sources including published literature, genomic sequence information, metabolic databases and transporter databases” as well as current culture hypotheses. This new resource will help in the study of unculturable bacteria. (13)
References
(1) Rebecca E. LaFond and Sheila A. Lukehart "Biological Basis for Syphilis" Departments of Pathobiology, Medicine, University of Washington, Seattle, Washington 2006 American Society for Microbiology link:http://cmr.asm.org/cgi/content/full/19/1/29?view=long&pmid=16418521#R182
(2) Gerbase, A. C., J. T. Rowley, D. H. Heymann, S. F. Berkley, and P. Piot. “Global prevalence and incidence estimates of selected curable STDs.” 1998 Sex. Transm. Infect. 74(Suppl. 1):S12-S16 link:http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=10023347&dopt=Abstract
(3) Watson-Jones, D., J. Changalucha, B. Gumodoka, H. Weiss, M. Rusizoka, L. Ndeki, A. Whitehouse, R. Balira, J. Todd, D. Ngeleja, D. Ross, A. Buve, R. Hayes, and D. Mabey. “Syphilis in pregnancy in Tanzania. I . Impact of maternal syphilis on outcome of pregnancy.” 2002 J. Infect. Dis. 186:940-947 link:http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=12232834&dopt=Abstract
(4) Greenblatt, R. M., S. A. Lukehart, F. A. Plummer, T. C. Quinn, C. W. Critchlow, R. L. Ashley, L. J. D'Costa, J. O. Ndinya-Achola, L. Corey, A. R. Ronald, et al. “Genital ulceration as a risk factor for human immunodeficiency virus infection.” 1988 AIDS 2:47-50 link:http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=3128996&dopt=Abstract
(5) Fraser CM, Norris SJ, Weinstock GM, White O, Sutton GG, Dodson R, Gwinn M, Hickey EK, Clayton R, Ketchum KA, Sodergren E, Hardham JM, McLeod MP, Salzberg S, Peterson J, Khalak H, Richardson D, Howell JK, Chidambaram M, Utterback T, McDonald L, Artiach P, Bowman C, Cotton MD, Fujii C, Garland S, Hatch B, Horst K, Roberts K, Sandusky M, Weidman J, Smith HO, Venter JC. “Complete genome sequence of Treponema pallidum, the syphilis spirochete.” Science. 1998 Jul 17;281(5375):324-5. link:http://www.sciencemag.org/cgi/content/abstract/281/5375/375?ijkey=d24dc3a13578671324655ff50f49ff64e81ff1b4&keytype2=tf_ipsecsha
(6) S J Norris “Polypeptides of Treponema pallidum: progress toward understanding their structural, functional, and immunologic roles.” Treponema Pallidum Polypeptide Research Group. Microbiol Rev. 1993 September; 57(3): 750–779. link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=372934
(7) Radolf, Justin D., Steiner, Bret and Shevchenko, Dimitriy. "Treponemea pallidum: doing a remarkable job with what it's got", Trends in Microbiology, v7 no.1, January, 1999. link:http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=10068990&dopt=Abstract
(8) Sell S, Gamboa D, Baker-Zander SA, Lukehart SA, Miller JN. “Host response to Treponema pallidum in intradermally-infected rabbits: evidence for persistence of infection at local and distant sites.” J Invest Dermatol. 1980 Dec;75(6):470-5. link:http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=7003026&dopt=Abstract
(9) Collart P, Franceschini P, Durel P. “Experimental rabbit syphilis.” Br J Vener Dis. 1971 Dec;47(6):389-400. link:http://iai.asm.org/cgi/content/abstract/58/9/3158?ijkey=d9c35091f3bd1e0781d4368f9b27c8e8b1a65a90&keytype2=tf_ipsecsha
(10) Marra, C., S. A. Baker-Zander, E. W. Hook III, and S. A. Lukehart. “An experimental model of early central nervous system syphilis.” 1991 J. Infect. Dis. 163:825-829 link:http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=2010635&dopt=Abstract
(11) Sheila A. Lukehart, Ph.D., Charmie Godornes, B.S., Barbara J. Molini, M.S., Patricia Sonnett, B.S., Susan Hopkins, M.D., Fiona Mulcahy, M.D., Joseph Engelman, M.D., Samuel J. Mitchell, M.D., Ph.D., Anne M. Rompalo, M.D., Christina M. Marra, M.D., and Jeffrey D. Klausner, M.D., M.P.H. “Macrolide Resistance in Treponema pallidum in the United States and Ireland” The New England Journal of Medicine. July 8 2004 link:http://content.nejm.org/cgi/content/full/351/2/154?ijkey=dabb0f6d7174c8db881353d130216ae720fed192&keytype2=tf_ipsecsha
(12) David E. Leslie,Franca Azzato, Theo Karapanagiotidis, Jennie Leydon, and Janet Fyfe “Development of a Real-Time PCR Assay To Detect Treponema pallidum in Clinical Specimens and Assessment of the Assay's Performance by Comparison with Serological Testing” Journal of Clinical Microbiology, January 2007, p. 93-96, Vol. 45, No. 1 link:http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17065262
(13) Hiroyuki Ogata* and Jean-Michel Claverie “Metagrowth: a new resource for the building of metabolic hypotheses in microbiology” Nucleic Acids Res. 2005 January 1; 33(Database Issue): D321–D324. link:http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15608207
Edited by Jasmin Eshragh, student of Rachel Larsen at UCSD.
KMG
