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The ability of tetracyclines to treat Lymphatic Filariasis by killing the endosymbiotic bacteria Wolbachia

The ability of tetracyclines to treat Lymphatic Filariasis by killing the endosymbiotic bacteria Wolbachia.

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The ability of tetracyclines to treat Lymphatic Filariasis by killing the endosymbiotic bacteria Wolbachia

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  1. The ability of tetracyclines to treat Lymphatic Filariasis by killing the endosymbiotic bacteria Wolbachia Rajan, T.V 2004. Relationship of Anti-microbial activity of Tetracyclines to their ability to block the L3 to L4 molt of the human filarial parasite Brugia malayi. American Journal of Tropical Medicine 7: 24-28. Hannah Dowling BIO 475

  2. Contents • Lymphatic Filariasis • Physiological Effects on humans • Mosquito life cycle • Treatments • Tetracyclines - Doxycycline • Conclusion

  3. Lymphatic Filariasis • Affects over 120 million people worldwide • Found mainly in the tropics of Africa, Asia, and Central America • Causes severe disabilities and lymphatic system destruction

  4. Physiological manifestations • Lymphedema, elephantiasis, hydrocele, and scrotal elephantiasis • The extremities can swell to several times their normal size, which, along with decreased lymphatic function, can lead to bacterial infections that the body cannot fight effectively

  5. Diagnosis • Microfilaremia levels can be detected in the blood only after prolonged infection by blood smear • The blood sample must be taken in accordance with the known periodicity of the microfilariae to achieve the most accurate results • Microfilariae are present in high numbers at night, when chances of transmission are high because of night-biting mosquitoes

  6. Transmission and Prevention • Transmitted by Culex, Anopheles, and Aedes Mosquitoes through a complex life cycle • Larvae in human ingested by mosquito, larvae mature and migrate to proboscis of mosquito, and move to new human host at mosquito’s next blood meal • Transmission prevented by use of mosquito spray (DEET) and bed nets

  7. Filariae • Filariae: Brugia malayi (limited to Asia), Wuchereria bancrofti (tropical areas worldwide), and Brugia timori (Indonesia) • 10cm long and measure 2cm in width • Can survive for up to 10 years and begin to reproduce approximately 6 to 12 months after infection Wuchereria bancrofti in a blood smear

  8. Wolbachia • Endosymbiotic bacteria found in up to 70% of arthropods • In filariae, they are constrained to the organisms’ hypodermis and the female reproductive tissues • Transmitted vertically • Gram-negative • Genome contains 1.1 million neucleotides

  9. Wolbachia Bacteria (Left) Cross-Section of a Female Worm from an Extirpated Nodule from a Patient with Onchocerciasis Wolbachia, endosymbiotic bacteria of filarial nematodes important for embryo development, are targets for antifilarial treatment. The bacteria here were stained with antibodies against Yersinia Hsp60. The bacteria are located in the hypodermis and oocytes of the worm (arrows). h, hypodermis; i, intestine; m, muscle; u, uterine tube. (Right) Cross Section of Wuchereria bancrofti, with arrows showing Wolbachia.

  10. Wolbachia • Genome contains genes necessary to make one nucleic acid and all necessary genes to infect new hosts and evade the host’s immune system • Lacks genes to produce lipopolysacharride but produces inflammatory reaction via TLR4 • Has genes that are necessary for the production of riboflavin, flavin adenine dinucleotide, and heme • Type IV secretion system

  11. Treatment • Wolbachia are present in the tissue responsible for synthesizing cuticle (the hypodermal syncitium) - may have a crucial role in the molting process of the filarial host • Diethylcarbamazine (DEC), Ivermectin, and Albendazole have microfilaricidal effects but no adulticidal effects

  12. Proportion of worms/larvae killed by the most common treatments (Data courtesy of Stolk et al., 2004)

  13. Tetracycline (Doxycycline) • Tetracycline inhibits the L3 to L4 molt of the larvae to completely stop reproduction • After continued treatment, it has limited macrofiliaricidal effects • More research is needed on the mechanism of effect and of the accompanying side effects

  14. Chemically Modified Tetracyclines • CMTs are tetracyclines that have had the diethylamino group attached to the fourth carbon of the A ring of the tetracycline molecule removed • This action removes the antimicrobial activity but has higher macrofiliaricidal effects than tetracyclines • CMTs are more potent but may be available for mass treatment and are still being researched

  15. Tetracycline vs. CMTs At high concentrations (10-20µg/mL), tetracycline completely blocked molting, but viability of the larvae was not affected. This means that the larvae are not molting but still can be seen in constant motion – which means they are not being killed by tetracycline. In experiments using Col-3 and Col-8 at the same high concentrations (10-20µg/mL), the larvae were killed within 24 hours. At much lower concentrations, Col-3 was shown to inhibit molting without interfering with the viability of the larvae (concentrations of 0.3µg/mL). (Charts courtesy of T.V. Rajan, 2004, The Lancet)

  16. Lanes 1-4 contain Wolbachia DNA ribosomal amplified (rDNA), and lanes 5-8 contain Brugia malayi collagen 1 Lanes 1,5: Medium Lanes 2,6: 0.5µg/mL Col-3 Lanes 3,7: 1µg/mL Col-8 Lanes 4,8: 50µg/mL tetracycline Amplification of Wolbachia DNA by PCR

  17. Results • Results showed that the amounts of Wolbachia DNA stayed relatively the same between the control group and those treated with CMTs • Although CMTs do not have anti-microbial properties, they are more potent than tetracyclines and may be more effective in mass administration

  18. Conclusion • More research is needed to find an appropriate method of treatment for this disease • Tetracyclines such as Doxycyline look most promising because they are proven to be safe and effective, but may not be given to entire populations because of the risk of resistance

  19. References • Babu B.V., A.N. Nayak, K. Rath, and A.S. Kerketta. 2005. Use of the Dermatology Life Quality Index in filarial lymphedema patients. Transactions of the Royal Society of Tropical Medicine and Hygiene 100: 258-263. • Centers for Disease Control and Prevention. 2004. Fact Sheet for the general public: Lymphatic Filariasis. Centers for Disease Control, Washington DC. • Cox, F.E.G. 2002. History of Human Parasitology. Clinical Microbiology Reviews 15: 595-612. • Critchley J., D. Addiss, H. Ejere, C. Gamble, P. Garner, and H. Gelband. 2005. Albendazole for the control and elimination of lymphatic filariasis: systematic review. Tropical Medicine and International Health 10: 818-825. • Dutton, T.J., and S.P. Sinkins. 2005. Filarial susceptibility and effects of Wolbachia in Aedes pseudoscutellaris mosquitoes. Medical and Veterinary Entomology 19: 60-65. • Goldstein, D.R. 2004. Toll-like receptors and other links between innate and acquired alloimmunity. Current Opinion in Immunology 16: 538-544. • Masui, S., S. Tetsuhiko, and H. Ishikawa. 2000. Genes for the Type IV Secretion System in an Intracellular Symbiont, Wolbachia, a causative agent of various Sexual Alterations in Arthropods. Journal of Bacteriology 182: 6529-6531. • Nielsen, N.O., P.E. Simonsen, P. Magnussen, S. Magesa, and H. Friis. 2005. Cross-Sectional relationship between HIV, lymphatic filariasis and other parasitic infections in adults in coastal northeastern Tanzania. Transactions of the Royal Society of Tropical Medicine and Hygiene 366: 1-9.

  20. References cont’d • Oqueka T., T. Supali, I.S. Ismid, Purnomo, P. Ruckert, M. Bradley, and P. Fischer. 2005. Impact of two rounds of mass drug administration using diethylcarbamazine combined with albendazole on the prevalence of Brugia timori and of intestinal helminthes on Alor Island, Indonesia. Filaria Journal 13:4:5. • Pfarr, K. and A. Hoerauf. 2005. The Annotated Genome of Wolbachia from the Filarial Nematode Brugia malayi: What it means for progress in Anti-filarial Medicine. PLoS Medicine 2: 289-292. • Punkosdy, G.A., D.G. Assiss, and P.J. Lammie. 2003. Characterization of Antibody responses to Wolbachia Surface Protein in Humans with Lymphatic Filariasis. Infection and Immunity 71: 5104-5114. • Rao R.U. 2005. Endosymbiotic Wolbachia of parasitic filarial nematodes as drug targets. Indian Journal of Medical Research 122: 199-204. http://www.icmr.nic.in/ijmr/2005/september/0901.pdf • Rao R.U., H. Moussa, and G.J. Weil. 2002. Brugia malayi: effects of antibacterial agents on larval viability and development in vitro. Experimental Parasitology 101: 77-81. • Rajan T.V. 2004. Relationship of Anti-microbial activity of tetracyclines to their ability to block the L3 to L4 molt of the human filarial parasite Brugia malayi. American Journal of Tropical Medicine 71: 24-28. • http://www.ajtmh.org/cgi/content/full/71/1/24 • Smith H.L., and T.V. Rajan. 2000. Tetracycline Inhibits Development of the Infective-Stage Larvae of Filarial Nematodes In Vitro. Experimental Parasitology 95: 265-270. • Sommer, A., P. Fischer, K. Krause, K. Boettcher, P.M. Brophy, R.D. Walter, and E. Liebau. 2001. A stress-responsive glyoxase I from the parasitic nematode Onchocerca volvulus. Biochemistry Journal 353: 445-452.

  21. References cont’d • Stolk, W.A., S.J. de Vlas, and J.D.F. Habbema. 2005. Anti-Wolbachia treatment for lymphatic filariasis. The Lancet 365: 2067-2068. • Taylor, M.J. and A. Hoerauf. 1999. Wolbachia Bacteria of Filarial Nematodes. Parasitology Today 15: 437-442. • Taylor, M.J., C. Bandi, A.M. Hoerauf, and J. Lazdins. 2000. Wolbachia Bacteria of Filarial Nematodes: A Target for control? Parasitology Today 16: 179-180. • from: http://www.itg.be/itg/DistanceLearning/LectureNotesVandenEndenE/41_Filariasisp3.htm. March 15, 2006. • Taylor M.J., H.F. Cross, L. Ford, W.H. Makunde, G.B.K.S. Prasad and K. Bilo. 2001. Wolbachia bacteria in filarial immunity and disease. Parasite Immunology 23: 401-409. • http://www.blackwell-synergy.com/doi/abs/10.1046/j.1365-3024.2001.00400.x • Taylor, M.J. 2002. Wolbachia Endosymbiotic Bacteria of Filarial Nematodes. A New Insight into Disease Pathogenesis and Control. Archives of Medical Research 33: 422-424. • Taylor, M.J. 2003. Wolbachia in the Inflammatory Pathogenesis of Human Filariasis. Annals of the New York Academy of Sciences 990: 444-449. • Taylor M.J., W.H. Makunde, H.F. McGarry, J.D. Turner, S. Mand, and A. Hoerauf. 2005. Macrofilaricidal activity after Doxycycline treatment of Wuchereria bancrofti: a double-blind, randomized placebo-controlled trial. Lancet 365: 2116-2117. • Tisch, D.J., E. Michael, and J.W. Kazura. 2005. Mass chemotherapy options to control lymphatic filariasis: a systematic review. Lancet Infectious Diseases 5: 514-523. • Vanden Enden, E. 2005. Lecture Notes: Lymphatic Filariasis – Prince Leopold Institute of Tropical Medicine, Belgium. Accessed

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