T. pallidum pallidum is a motile spirochaete that is generally acquired by close sexual contact, entering the host via breaches in squamous or columnar epithelium. The organism can also be transmitted to a fetus by transplacental passage during the later stages of pregnancy, giving rise to congenital syphilis. The helical structure of T. pallidum pallidum allows it to move in a corkscrew motion through a viscous medium such as mucus. It gains access to host's blood and lymph systems through tissue and mucous membranes. The subspecies causing yaws, pinta, and bejel are morphologically and serologically indistinguishable from T. pallidum pallidum (syphilis); however, their transmission is not venereal in nature and the course of each disease is significantly different (Wiki: T. pallidum).
4. Microbial Pathogenesis
T. pallidum (in the case of syphilis) generally first forms a chancre at the site of infection and the spirochetes are infectious. The bacteria then penetrate mucosal membranes, and invade the bloodstream as well as other tissues. The bacteria cause latent syphilis which can progress into tertiary syphilis by the bacteria causing inflammatory disease and thus creating problems in infected (Salyers and Whitt., 2002).
5. Host Ranges and Animal Models
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. 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 (MicrobeWiki: T. pallidum).
6. Host Protective Immunity
The primary clearance mechanism responsible for removal of T. pallidum from syphilitic chancres is believed to be antibody‐mediated treponemal opsonization and subsequent phagocytosis and killing by macrophages (Cameron et al., 1998).
II. Vaccine Related Pathogen Genes
1. GlpQ
Gene Name :
GlpQ
Sequence Strain (Species/Organism) : Treponema pallidum subsp. pallidum str. Nichols
Molecule Role Annotation :
Immunization with the recombinant GlpQ significantly protected rabbits from subsequent T. pallidum challenge, altering lesion development at the sites of challenge (Cameron et al., 1998).
Molecule Role Annotation : Treponema pallidum-susceptible guinea pigs of strain C4D were immunized with recombinant T. pallidum antigen TmpB. Guinea pigs receiving TmpB antigen demonstrated protection expressed by the development of significantly (P less than 0.01) smaller, atypical lesions of significantly (P less than 0.01) shorter duration and devoid of or containing fewer T. pallidum organisms than lesions in the remaining immunized and control animals (Wicher et al., 1991).
Molecule Role Annotation :
Immunization with recombinant Tp92 partially protected rabbits from subsequent T. pallidum challenge (Cameron et al., 2000).
>WP_010882482.1 DNA starvation/stationary phase protection protein [Treponema pallidum]
MNMCTDGKKYHSTATSAAVGASAPGVPDARAIAAICEQLRQHVADLGVLYIKLHNYHWHIYGIEFKQVHE
LLEEYYVSVTEAFDTIAERLLQLGAQAPASMAEYLALSGIAEETEKEITIVSALARVKRDFEYLSTRFSQ
TQVLAAESGDAVTDGIITDILRTLGKAIWMLGATLKA
Molecule Role :
Protective antigen
Molecule Role Annotation :
immunization with the r4D Ag alters the course of experimental syphilis in a manner consistent with previously defined parameters of partial protection. (Borenstein et al., 1988)
The reactivities of TpF1 with syphilitic sera were proportional to the titers of the T. pallidum particle agglutination (TPPA) assay. These data indicate that the recombinant protein TpF1 is a highly immunogenic protein in human and rabbit infections and a promising marker for the screening of syphilis.(Jiang et al., 2013)
Molecule Role Annotation :
These results demonstrate that epitopes in fragment 1 are recognized by T cells and antibodies during infection and that immunization with this portion of TprK most effectively attenuates syphilitic lesion development.(Morgan et al., 2002) N-terminal conserved region of TprF elicits strong T-cell responses during infection with different T. pallidum subsp. pallidum isolates(Sun et al., 2004)
Vaccination Protocol:
Rabbits were immunized three times (IM, SC, IP, and ID) at 3-week intervals with the Ribi MPL + TDM + CWS adjuvant and 100 μg of purified inclusion bodies from E. coli expressing either the pET-3a vector alone or the Gpd-pET-3a construct (Cameron et al., 1998).
Challenge Protocol:
Two weeks after administration of the final immunization, rabbits were challenged ID at each of six sites on their shaved backs with 103 T. pallidum per site (Cameron et al., 1998).
Efficacy:
Immunization with the recombinant GlpQ significantly protected rabbits from subsequent T. pallidum challenge, altering lesion development at the sites of challenge. All eight control rabbits developed typical red, raised, and highly indurated lesions at each of the six challenge sites that in some cases progressed to ulceration. All four of the Gpd-immunized rabbits developed atypical pale, flat, slightly indurated, and nonulcerative reactions at each of the six challenge sites. In all cases, induration in the Gpd-immunized animals resolved before lesions appeared in the control animals and resembled delayed-type hypersensitivity responses more than typical syphilis chancres (Cameron et al., 1998).
Vaccination Protocol:
In the first set of experiments, guinea pigs assigned randomly to seven groups of five animals each were immunized with TmpA, TmpB, TmpC, TmpA plus TmpB plus TmpC (TmpABC), or E. coli membranes. Five animals received adjuvant in phosphate-buffered saline, and five guinea pigs served as nonimmunized control. Each animal received six injections, each of 100 μg of antigen in a 0.4-ml volume, distributed in two subcutaneous injections (0.15 ml each) in the inguinal lymph nodes areas and one intraperitoneal injection (0.1 ml) (Wicher et al., 1991).
Challenge Protocol:
A week after immunizing injection 6, all animals, including untreated controls, were injected intradermally in a hind leg with 100 μl of suspension containing 3 X 10^6 T. pallidum Nichols freshly extracted from rabbit testes.
Efficacy:
Guinea pigs receiving TmpB antigen demonstrated protection expressed by the development of significantly (P less than 0.01) smaller, atypical lesions of significantly (P less than 0.01) shorter duration and devoid of or containing fewer T. pallidum organisms than lesions in the remaining immunized and control animals (Wicher et al., 1991).
Vaccination Protocol:
New Zealand White rabbits were immunized (intramuscularly, subcutaneously, intraperitoneally, and intradermally) at 3‐week intervals with Ribi adjuvant and 125 μg of purified intact ORF recombinant Tp92. Unimmunized rabbits were used as a control (Cameron et al., 2000).
Challenge Protocol:
At 1–4 weeks after administration of the final immunization in each protection experiment, the immunized rabbits and a total of 4 unimmunized control rabbits were subjected to intradermal challenge at each of 8 sites on their shaved backs with 10^5 T. pallidum subsp. pallidum (Nichols strain) per site. The rabbits were examined daily to monitor the development, morphologic appearance, and progression of lesions appearing at the challenge sites (Cameron et al., 2000).
Efficacy:
Immunization with recombinant Tp92 partially protected rabbits from subsequent T. pallidum challenge. the rabbits immunized with the T. pallidum recombinant Tp92 before challenge all demonstrated alteration of lesion development. Significant attenuation of lesion development was observed in these rabbits, with atypical pale, flat, slightly indurated, and for the most part, nonulcerative lesions appearing at the sites of challenge. In these protection experiments, the number of lesions progressing to ulceration and the number of darkfield‐positive lesions in the Tp92‐immunized rabbits were significantly smaller than those of lesions appearing in the control animals (Cameron et al., 2000).
IV. References
1. Borenstein et al., 1988: Borenstein LA, Radolf JD, Fehniger TE, Blanco DR, Miller JN, Lovett MA. Immunization of rabbits with recombinant Treponema pallidum surface antigen 4D alters the course of experimental syphilis. Journal of immunology (Baltimore, Md. : 1950). 1988; 140(7); 2415-2421. [PubMed: 2450921].
2. Brautigam et al., 2016: Brautigam CA, Deka RK, Liu WZ, Norgard MV. The Tp0684 (MglB-2) Lipoprotein of Treponema pallidum: A Glucose-Binding Protein with Divergent Topology. PloS one. 2016; 11(8); e0161022. [PubMed: 27536942].
3. Cameron et al., 1998: Cameron CE, Castro C, Lukehart SA, Van Voorhis WC. Function and protective capacity of Treponema pallidum subsp. pallidum glycerophosphodiester phosphodiesterase. Infection and immunity. 1998; 66(12); 5763-5770. [PubMed: 9826352].
4. Cameron et al., 1998: Cameron CE, Castro C, Lukehart SA, Van Voorhis WC. Function and protective capacity of Treponema pallidum subsp. pallidum glycerophosphodiester phosphodiesterase. Infection and immunity. 1998; 66(12); 5763-5770. [PubMed: 9826352].
5. Cameron et al., 2000: Cameron CE, Lukehart SA, Castro C, Molini B, Godornes C, Van Voorhis WC. Opsonic potential, protective capacity, and sequence conservation of the Treponema pallidum subspecies pallidum Tp92. The Journal of infectious diseases. 2000; 181(4); 1401-1413. [PubMed: 10762571].
6. Cameron et al., 2000: Cameron CE, Lukehart SA, Castro C, Molini B, Godornes C, Van Voorhis WC. Opsonic potential, protective capacity, and sequence conservation of the Treponema pallidum subspecies pallidum Tp92. The Journal of infectious diseases. 2000; 181(4); 1401-1413. [PubMed: 10762571].
7. Centurion-Lara et al., 1997: Centurion-Lara A, Arroll T, Castillo R, Shaffer JM, Castro C, Van Voorhis WC, Lukehart SA. Conservation of the 15-kilodalton lipoprotein among Treponema pallidum subspecies and strains and other pathogenic treponemes: genetic and antigenic analyses. Infection and immunity. 1997; 65(4); 1440-1444. [PubMed: 9119485].
8. Centurion-Lara et al., 1999: Centurion-Lara A, Castro C, Barrett L, Cameron C, Mostowfi M, Van Voorhis WC, Lukehart SA. Treponema pallidum major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response. The Journal of experimental medicine. 1999; 189(4); 647-656. [PubMed: 9989979].
9. Clark et al., 1993: Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature. 1993; 364(6436); 412-420. [PubMed: 8332212].
10. Jiang et al., 2013: Jiang C, Zhao F, Xiao J, Zeng T, Yu J, Ma X, Wu H, Wu Y. Evaluation of the recombinant protein TpF1 of Treponema pallidum for serodiagnosis of syphilis. Clinical and vaccine immunology : CVI. 2013; 20(10); 1563-1568. [PubMed: 23945159].
11. Kao et al., 2017: Kao WA, P?troov H, Ebady R, Lithgow KV, Rojas P, Zhang Y, Kim YE, Kim YR, Odisho T, Gupta N, Moter A, Cameron CE, Moriarty TJ. Identification of Tp0751 (Pallilysin) as a Treponema pallidum Vascular Adhesin by Heterologous Expression in the Lyme disease Spirochete. Scientific reports. 2017; 7(1); 1538. [PubMed: 28484210].
12. Lithgow et al., 2017: Lithgow KV, Hof R, Wetherell C, Phillips D, Houston S, Cameron CE. A defined syphilis vaccine candidate inhibits dissemination of Treponema pallidum subspecies pallidum. Nature communications. 2017; 8; 14273. [PubMed: 28145405].
13. McGill et al., 2010: McGill MA, Edmondson DG, Carroll JA, Cook RG, Orkiszewski RS, Norris SJ. Characterization and serologic analysis of the Treponema pallidum proteome. Infection and immunity. 2010; 78(6); 2631-2643. [PubMed: 20385758].
15. Morgan et al., 2002: Morgan CA, Lukehart SA, Van Voorhis WC. Immunization with the N-terminal portion of Treponema pallidum repeat protein K attenuates syphilitic lesion development in the rabbit model. Infection and immunity. 2002; 70(12); 6811-6816. [PubMed: 12438357].
16. Salyers and Whitt., 2002: Abigail A. Salyers, Dixie D. Whitt. The Spirochetes: Borrelia burgdorferi and Treponema pallidum. 197-99. Bacterial Pathogenesis: A Molecular Approach. 2002. ASM Press, Washington D.C. USA.
17. Sun et al., 2004: Sun ES, Molini BJ, Barrett LK, Centurion-Lara A, Lukehart SA, Van Voorhis WC. Subfamily I Treponema pallidum repeat protein family: sequence variation and immunity. Microbes and infection. 2004; 6(8); 725-737. [PubMed: 15207819].
18. Tomson et al., 2007: Tomson FL, Conley PG, Norgard MV, Hagman KE. Assessment of cell-surface exposure and vaccinogenic potentials of Treponema pallidum candidate outer membrane proteins. Microbes and infection. 2007; 9(11); 1267-1275. [PubMed: 17890130].
19. Wicher et al., 1991: Wicher K, Schouls LM, Wicher V, Van Embden JD, Nakeeb SS. Immunization of guinea pigs with recombinant TmpB antigen induces protection against challenge infection with Treponema pallidum Nichols. Infection and immunity. 1991; 59(12); 4343-4348. [PubMed: 1937794].
20. Wicher et al., 1991: Wicher K, Schouls LM, Wicher V, Van Embden JD, Nakeeb SS. Immunization of guinea pigs with recombinant TmpB antigen induces protection against challenge infection with Treponema pallidum Nichols. Infection and immunity. 1991; 59(12); 4343-4348. [PubMed: 1937794].
