Introduction - The Trichomonas vaginalis Genome Database

Human trichomoniasis is a sexually transmitted infection caused by the protozoan parasite Trichomonas vaginalis. This infection is the most common non-viral sexually transmitted disease worldwide. Infection often leads to vaginitis and accute inflammatory disease of the genital mucosa. Trichomoniasis is associated with preterm delivery, low birthweight and increased infant mortality. Infection also pre-disposes individuals to HIV/AIDS and cervical cancer (Cohen, 2000; Upcroft and Upcroft, 2001). T. vaginalis has also been reported in the urinary tract, fallopian tubes and pelvis, and can cause pneumonia, bronchitis and oral lesions.

Trichomonas vaginalis is the most prevalent parasite found in North America, where it is responsible for approximately 5 million cases of vaginitis annually. Worldwide, over 170 million cases of trichomoniasis are reported each year (World Health Organization, 1998). Infection rates have been reported as high as 67% in Mongolia in 1988 (Schwebke et al., 1998), 40-60% in Africa. and 40% in Indigenous Australians over 40 years of age (Bowden et al., 1999). Trichomoniasis rates are also high in inner city populations in the United States.

Tritrichomonas foetus is a closely related parasite that infects cattle and causes significant agricultural problems. This trichomonad is sexually-transmitted and can be found throughout the reproductive tract and is the maternal and fetal components of the placenta of cows. Infection with this parasite may cause metritis, early embryonic death, abortion, pyometra, and infertility (Bondurant, 1997; Corbeil, 1999). Reported prevalence rates in the US vary from 12% to 44% and the disease causes considerable economic loss (Bondurant, 1990; Rae et al., 1999).

BASIC BIOLOGY & LIFE CYCLE

T. vaginalis is a flagellated protozoan possessing five flagella four of which are located at its anterior portion. The fifth flagellum is incorporated within the undulating membrane of the parasite. T. vaginalis is anaerobic and therefore contains no mitochondria in its cytoplasm. Instead, specialized granules called hydrogenosomes are distributed throughout the region of the cytoplasm adjacent to the hyaline, pointed axostyle that protrudes from the posterior of the parasite. In accord with its anaerobic state, T. vaginalis derives its carbon from reduction of glycogen and glucose into succinate, acetate, malate and hydrogen. In addition, it produces some carbon dioxide, but not via the Krebs cycle pathway.

Although cell division in T. vaginalis has been extensively described, the lifecycle of the parasite is still poorly understood. T. vaginalis is known to exist only as a trophozoite and appears to lack a cystic stage. The trophozoite lives in close association with the epithelium of the urogenital tract and reproduces by binary fission. The infection is usually transmitted by sexual intercourse and continual re-infection of one sexual partner by the otheris common. Newborn girls can acquire the infection from their infected mothers during passage through the birth canal. In such cases, the infection tends to remain asymptomatic until puberty.

PHYLOGENETICS OF T. vaginalis

T. vaginalis, Entamoeba histolytica, and Giardia lamblia are three lumenal parasites with a remarkable number of common features, which has led to the proposal that they form a separate kingdom called the Archezoa (Cavalier-Smith, 1987). These three extracellular, anaerobic parasites (1) must adhere to

the lumen of the host to survive (2) carry-out fermentive carbohydrate metabolism and (3) lack mitochondria (Plumper et al., 1998; Dyall et al.,2000). Interestingly, evidence exists that all three once contained a mitochondrion, or the precursor of a mitochondrion and have since lost or highly modified this organelle. Phylogenetic studies on selected nuclear genes of these organisms indicate that these genes were derived from the endosymbiont that gave rise to mitochondria, via lateral gene transfer (Bui, et al., 1996; Germot et al., 1996; Horner, et al., 1996; Roger et al., 1996; Dyall et al., 2000; Roger et al., 1998; Clark and Roger, 1995). Given the phylogenetic position of T. vaginalis and G. lamblia at the base of the eukaryotic tree, these findings imply that the first eukaryotic cell contained the precursor to mitochondria, contrary to previous suggestions that this endosymbiotic event occurred after the evolution of an endomembrane system/ER and the nucleus.

THE HYDROGENOSOME

Unlike G. lamblia and E. histolytica, T. vaginalis contains an enigmatic organelle, involved in carbohydrate metabolism, called the hydrogenosome (Muller, 1993; Johnson et al., 1993). No organelle involved in carbohydrate metabolism is apparent in G. lamblia whereas an organelle of unknown function, the mitosome/crypton, has recently been discovered in E. histolytica (Mai et al., 1999; Tovar et al., 1999). It is unclear what, if any, relationship the mitosome may have to hydrogenosomes and or mitochondria. In contrast, gene phylogenies and studies on organelle biogenesis of hydrogenosomes strongly indicate that this organelle evolved from the same alpha-probacterial endosymbiont that gave rise to mitochondria. T. vaginalis proteins that are phylogenetically similar to mitochondria are localized in hydrogenosomes and these two organelles appear to employ similar targeting mechanisms for biogenesis (Dyall and Johnson, 2000). To date, no form of genetic material has been localized within the hydrogenosome (Clemens and Johnson, 2000).

TREATMENT AND DRUG RESISTANCE

Trichomoniasis is treated with a relatively cheap and effective 5-nitroimidizole derivative called Metronidazole. This is the only drug licensed by the U.S. Food and Drug Administration for treatment. A large increase in Metronidazole refractory Trichomonas was reported in the U.S. in the late 1990's (Sobel et al., 1999). Metronidazole is administered in an inactive form and must be modified in the hydrogenosome to become cytotoxic (Land and Johnson, 1999). Results from studies performed in several labs indicate a strong correlation between the loss or reduction of hydrogenosomal proteins involved in drug activation and drug resistance. Furthermore, modified expression of these crucial proteins is accompanied by reduced transcription of their genes (Quon et al., 1992; Land et al., 2001). These findings strongly correlate Metronidazole resistance with decreased intracellular levels of proteins needed for drug activation.

TRICHOMONIASIS AND HIV

Trichomonas vaginalis is emerging as one of the most important cofactors in amplifying HIV transmission, particularly in African-American communities of the United States (Sorvillo et al., 2001. Individuals infected with T. vaginalis have a significantly increased incidence of HIV transmission (Jackson et al., 1997; Cohen et al., 1997; Sorvillo et al., 1998). T. vaginalis elicits and aggressive local cellular immune response with a heavy influx of target cells for HIV. This response may increase the chance of portal entry of HIV in a seronegative individual. Conversely, in an HIV-seropositive individual, puntate hemorrages that are frequently associated with T. vaginalis infection, increase shedding and subsequent transmission of the virus (Cohen et al., 1997). The ability to rapidly identify potential vaccine candidates for T. vaginalis, based on the availability of genome sequence, could ultimately contribute to decreased HIV infection rates worldwide.

REFERENCES

Bondurant, R.H. (1997). Pathogenesis, diagnosis and management of trichomoniasis in cattle. Veterinary Clinics of North America, Food and Animal Practice 13:345-361.

Bondurant, R.H., Anderson, M.L., Blanchard, P., Hird, D., Danaye-Elmi, C., Palmer, C., Sischo, W.M., Suther, D., Utterback, W. and Weigler, B.J. (1990). Prevalence of trichomoniasis among California beef herds. J. Am. Vet. Med. Assoc. 196: 1590-1593.

Bowden, F.J., Paterson, B.A., Mein, J., Savage, J., Fairley, C.K., Garland, S.M., and Tabrizi, S.N. (1999). Estimating the prevalence of Trichomonas vaginalis, Chlamydia trachomatis, Nisseria gonorrhoeae, and human papilloma virus infection in indigenous women in northern Australia. Sex. Transm. Inf. 75:431-4.

Bui, E.T.N., Bradley, P.J., and Johnson, P.J. (1996). A common evolutionary origin for mitochondria and hydrogenosomes. Proc. Nat. Acad. Sci.USA 93:9651-9656.

Cavalier-Smith, T. (1987) The simultaneous symbiotic origin of mitochondria, chloroplasts and microbodies. Ann. N.Y. Acad. Sci. 503:55-71.

Clark, C.G. and Roger, A.J. (1995). Direct evidence for secondary loss of mitochondria in Entamoeba histolytica. Proc. Nat. Acad. Sci.USA 92:6518-6521.

Clemens, D.L. and Johnson, P.J. (2000). Failure to detect DNA in hydrogenosomes of Trichomonas vaginalis by nick translation and immunomicroscopy. Mol. Biochem. Parasitol. 106: 307-313.

Cohen, J. (2000). HIV transmission - AIDS researchers look to Africa for new insights. Science 287:942.

Corbeil, L.B. (1999). Immunization and diagnosis in bovine reproductive tract infections V. TriTrichomonas foetus infection. In W.J. Dodds (ed.) Advances in Veterinary Medicine , vol 41 Veterinary vaccines and diagnosticsm, Ronald D. Schultz (ed.). p. 224-233. Academic Press, San Diego, CA.

Dyall, S.D., Koehler, C.M., Delgadillo-Correa, M.G., Bradley, P.J., Plumper, E., Leuenberger, D., Turck, C.W., and Johnson, P.J. (2000). Presence of a member of the mitochondrial carrier family in hydrogenosomes: conservation of membrane targeting pathways between hydrogenosomes and mitochondria. Mol. Cell Biol. 20:2488-2497.

Dyall, S.D. and Johnson, P.J. (2000). Origins of hydrogenosomes and mitochondria: evolution and organelle biogenesis. Curr. Op. Microbiol. 3:404-411.

Germot, A., Philippe, H., and Le Guyader, H. (1996). Presence of a mitochondrial-type 70-kDa heat shock protein in Trichomonas vaginalis suggests a very early mitochondrial endosymbiosis in eukaryotes. Proc. Natl. Acad. Sci, USA 93:14614-14617.

Horner, D.S., Hirt, R.P., Kilvington, S., Lloyd,D., and Embley, T.M. (1996). Molecular data suggest an early acquisition of the mitochondrion endosymbiont. Proc. R. Soc. Lond. B. Biol. Sci. 263:1053-1059.

Johnson, P.J., Lahti, C.J., and Bradley, P.J. (1993). Biogenesis of the hydrogenosome in the anaerobic protist Trichomonas vaginalis. J. Parasitol. 79:644-670.

Mai, Z., Ghosh, S., Frisardi, M., Rosenthal, B., Rogers, R., Samuelson, J. (1999). Hsp60 is targeted to a cryptic mitochondrion-derived organelle ("crypton") in the macroaerophilic protozoan parasite Entamoeba histolytica. Mol. Cell Biol.. 19:2198-2205.

Muller, M. (1993). The Hydrogenosome. J. Gen. Micro. 139:2879-2889.

Plumper, E., Bradley, P.J., Johnson, P.J. (1998). Implications of protein import on the origin of hydrogenosomes. Protist. 149:303-311.

Rae, D.O., Chenoweth, P.J., Genho, P.C., McIntosh, A.D., Crosby, E. and Moore, S.A. (1999). Prevalence of TriTrichomonas foetus in a bull populations and effect on production in a large cow-calf enterprise. JAVMA 214:1051-1055.

Roger, A.J., Clark, C.G. and Doolittle, W.F. (1996). A possible mitochondrial gene in the early- branching amitochondriate protist Trichomonas vaginalis. Proc. Natl. Acad. Sci. USA 93:14618-14622.

Roger, A.J., Svard, S.G., Tovar, J., Clark, C.G., Smith, M.W., Gillin, F.D., and Sogin, M.L. (1998). A mitochondrial-like chaperonin 60 gene in Giardia lamblia: evidence that diplomonads once harbored an endosymbiont related to the progenitor of mitochondria. Proc. Nat. Acad. Sci. USA 95:229-234.

Schwebke, J.R., Aira, T., Jordan, N., Jolly, P.E., and Vermund, S.H. (1998) Sexually transmitted diseases in Ulaanbaatar, Mongolia. Int. J. STD AIDS 9:354-358.

Sobel, J.D., Nagappan, V., and Nyirjesy, P. (1999). Metronidazole-resistant vaginal trichomoniasis - an emerging problem. New Eng. J. Med.341:292-293.

Tovar, J., Fischer, A., and Clark, G.C. (1999). The mitosome, a novel organelle related to mitochondria in an amitochondrial parasite Entamoeba histolytica. Mol. Microbiol. 32:1013-1021.

Upcroft, P. and Upcroft, J.A. (2001). Drug targets and mechanisms of resistance in the anaerobic protozoa. Clin. Microbiol. Rev. 14:150-164.