The use of antibiotics on Wolbachia as treatment for filarial diseases
Wolbachia is an endosymbiont that lives in many insects and arthropods. It also lives within Brugia malayi, a filarial nematode that can cause lymphatic filariasis, and Onchocerca volvulus, adifferent filarial nematode that causes onchocerciasis. Due to the symbiotic relationship that makes these organisms’ processes so specialized and heavily dependent on each other for survival, treatment of Wolbachia with antibiotics is a possible target for antifilarial activities. Thus recent research looks for new modes of action for novel antibiotics to treat filarial caused diseases to possibly prevent Wolbachia from reaching antibiotic resistance. This field is a rapidly growing research area with many more discoveries to be made and questions to answer.
Symbiotic Relationship
Past research has shown that the removal of Wolbachia from the host filarial nematodes causes antifilarial effects.1 To understand why this event occurs, the evolution of the symbiotic relationship between host and endosymbiont must be understood. This knowledge could lead to new antibiotic treatments as the mechanisms behind the proliferation and transmission of Wolbachia through the life cycle of the host can lead to novel targets for antibiotics.
Localization of Wolbachia
Wolbachia is found in stages of larval development in the hypodermal cells of the lateral cords as well as in the embryos of female filarial nematodes. 2 Past studies dating back to the late 1990's and early 2000's have shown that Wolbachia is transmitted by female Drosophila melanogaster to offspring by localizing in the posterior female host oocytes, thus increasing its chance to be incorporated into the germline and be passed off to the offspring. More recent studies on Drosophila have determined the mechanism to be related to the bacteria’s ability to use Drosophila microtubules, kinesin and dynein in insects to properly segregate to the maternal hosts' posterior germline pole plasma area during oogenesis. 3 4
Wolbachia uses a similar mechanism in both Drosophila and filarial nematodes. Wolbachia localizes to maternal centromeres during division. It is also found near the microtubules, which could be interpreted as a possible interaction between Wolbachia and the microtubules. 2 A dynein-based mechanism is used to Wolbachia make localize to the posterior of the cell.
Removal of Wolbachia from the filarial nematode host leads to large scale occurrences of apoptosis in the adult germline, and in the somatic cells in certain stages of nematode development leading up to the adult stage.5 The apoptosis in the uterine area results in sterilization of the adult female worms, as the embryos in uterus undergo apoptosis. This considerably reduces the adult worms' ability to spread and cause filarial diseases. Microfilaria are able to remain motile and viable, but are limited in their ability to develop past the L4 larvae stage and thus be able to reach a reproductive age and help the proliferation of more nematodes, an effect caused by apoptosis from the removal of Wolbachia through antibiotics.5 It was also found that Wolbachia uses A-P polarity to localize to the posterior of the egg and thus the beginning of the germline. Wolbachia is needed for the proper A-P polarity in the filarial nematodes, showing the necessity of Wolbachia to localize in the filarial nematodes' oocytes for normal embryo development. 2 Both of these findings could explain how the removal of Wolbachia leads to sterilization of female filarial nematodes.
Pathogenesis
Wolbachia can create a proinflammatory response with interaction with specific immunne cells. 1 Wolbachia creates an ineffective neutrophil response by preventing the disperal of eosinophils. 1. The Wolbachia stimulate the production of chemotactic cytokines that determine the neutrophil recruitment. When these neutrophils engulf the Wolbachia containing filarial nematodes, it stimulates the production of more chemotactic cytokines and thus a greater neutrophil recruitment pull. The large numbers of neutrophils release toxins, resulting in detrimental effects to nearby cells that regulate corneal functions.6 This event shows how Wolbachia can contribute to onchocerciasis.
At right is a sample image insertion. It works for any image uploaded anywhere to MicrobeWiki. The insertion code consists of:
Double brackets: [[
Filename: Ebola virus 1.jpeg
Thumbnail status: |thumb|
Pixel size: |300px|
Placement on page: |right|
Legend/credit: Electron micrograph of the Ebola Zaire virus. This was the first photo ever taken of the virus, on 10/13/1976. By Dr. F.A. Murphy, now at U.C. Davis, then at the CDC.
Closed double brackets: ]]
Other examples:
Bold
Italic
Subscript: H2O
Superscript: Fe3+
Overall paper length should be 3,000 words, with at least 3 figures with data.
Effectiveness of Antibiotic Treatments
Antibiotics have been seen to affect filarial nematodes due to their symbiotic relationship with Wolbachia.1 However, these treatments differ in efficacy, depletion of the filarial nematode, and the duration and dosage of treatment.
The depletion of Wolbachia by tetracycline class results in sterilization of the female filarial nematode. 1 Another derivative of the tetracycline class, doxycycline, results in a block in development of the filarie in the host, preventing it the parasites from reaching a reproducive age to proliferate the disease. 1 Rifampicin, oxytetracycline, and chloromphenicol all affect the filarial nematodes’ abilities to move, thus inihibit it spreading as effectively.7
Thus far, long dose treatments of doxcycline seem to be most effective in treating these tropical diseases: treatment of 100 mg/day for six weeks showed full Wolbachia and sterilization of female filarial nematodes for 18 months, while 200 mg/day for 4 – 6 weeks showed detrimental effects towards filarial nematodes.[ http://www-ncbi-nlm-nih-gov.ccl.idm.oclc.org/pmc/articles/PMC2668626/ 8] However, the doxycycline can disrupt bone and teeth development, making it unsafe for children and pregnant women to use.9 Due to its long duration treatments and its inability to be safe for all people to use, doxycycline is unsuitable via mass drug administration.10 Therefore, other combinations of effective treatments are being evaluated as an alternative to doxycycline that are suitable for mass drug administration.
Shorter treatments of rifampicin were tested to see if this antibiotic treatment would serve as an effective alternative for long duration and dose treatments of doxycycline. It was found that 10 mg/kg/day of rifampicin treatments for 2- and 4-week the Wolbachia inside O. volvulus, resulted in decrease in filarial activity but not to degree seen in doxycycline treatments. Thus it might be more effective to looking into treatments that use both doxycycline and rifampicin.11
It was tested to see whether combinations rifampicin and oxytetracycline would be effective treatments. The results showed that oxytetracycline treatments alone were the most effective in affecting the filarial nematodes, with a six month treatment with monthly dosing being the most effective, but 3 week and 6 week treatments also showing detrimental effects to filarial nematodes. However, rifampin alone and oxytetracycline-rifampin treatments showed at most borderline noticeable effects on the nematodes.12 Therefore, it may be better to look into other treatments that do not include rifampicin. The antibiotic had shown promise as an effective treatment for these diseases.11 However, it may be possible that those levels of efficacy are not replicable or the Wolbachia is already developing antibiotic resistance to rifampicin.
However, the most recent find in effective antibiotic treatments may say otherwise. One group looked at repurposing antibiotics. They found that 69 out of 121 compounds that showed in vitro activity towards filarial nematodes were seen as possible effective targets for removing Wolbachia from these nematodes.10 Using this information, 4 out of 15 selected compounds were found to show in vivo activity. These treatments came from the
fluoroquinolone, tetracycline, and classes.10 One of the most surprising results showed that ciprofloxacin from the fluoroquinolone class showed detrimental effects towards filarial activity. This finding is contradictory to earlier studies testing ciprofloxacin as an effective treatment for these tropical diseases.10 Thus it is possible that Wolbachia may have lost its antibiotic resistance towards this specific antibiotic and opens up possibilities to new research and more treatments that may have been overlooked to its inconsistencies in removing the Wolbachia. This particular study has shown that there is much more to learned about this phenomena and much more research to be done to fully understand the depth of the symbiotic relationship and treatments. Mechanisms of action for the identified 69 compounds that showed in vitro activity still have yet to be discovered. This area of research is rapidly evolving and expanding, with new questions popping up along the way.
Section 3
Include some current research in each topic, with at least one figure showing data.
Further Reading
[Sample link] Ebola Hemorrhagic Fever—Centers for Disease Control and Prevention, Special Pathogens Branch
References
3. (Ferree et al., 2005)[ http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.0010014 Ferree, P. M., Frydman, H. M., Li, J. M., Cao, J., Wieschaus, E., & Sullivan, W. (2005). <italic>Wolbachia</italic> Utilizes Host Microtubules and Dynein for Anterior Localization in the <italic>Drosophila</italic> Oocyte. PLoS Pathog, 1(2), e14. Retrieved from http://dx.plos.org/10.1371%2Fjournal.ppat.0010014 Gillette-Ferguson, I., Hise, A. G., McGarry, H. F., Turner, J., Esposito, A., Sun, Y., … Pearlman, E. (2004). Wolbachia-Induced Neutrophil Activation in a Mouse Model of Ocular Onchocerciasis (River Blindness). Infection and Immunity , 72 (10 ), 5687–5692. doi:10.1128/IAI.72.10.5687-5692.2004
Edited by Nitin Kuppanda, a student of Suzanne Kern in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2015.
