Attacking Filarial Worms By Killing Bacteria

Lymphatic filariasis and onchocerciasis are tropical diseases affecting approximately 150 million people between them. The symptoms are horrific, lymphatic filariasis results from blockage of the lymphatic system which eventually causes elephantiasis, whilst onchocerciasis causes skin lesions, and later “River Blindness”. Although the symptoms of these diseases are different, they share a similar cause, both are caused by infections of nematode worms - Brugia malayi and Wuchereria bancrofti in the case of filariasis, and Onchocerca volvulus for onchocerciasis.

There are no vaccines against either disease, though one is being trialled for the cattle form of onchocerciasis. There are however drugs that can be used against these worms, such as ivermectin, albendazole, and diethylcarbamazine. These drugs have been of immense value in reducing levels of disease in the population, but they have a fundamental weakness, they only affect the first-stage larvae, the microfilariae. These are the transmissive form so although excellent for mass dosing programmes to remove the disease from populations, the drugs are of little use for individuals that already have mature worms, which can live for up to 15 years. 

A standard treatment for individuals who have filarial worms is not an anti-parasitic drug, it is perhaps surprisingly, an antibiotic, doxycycline. Doxycycline does not affect the worm as such, it attacks a symbiotic bacteria within the worm, a strain of Wolbachia, (Slatko et al 2014). These bacteria live within the lateral cord and reproductive tracts of the worms and are also probably secreted into the patient, leading to increased inflammation and discomfort. If Wolbachia can be removed, the worms become infertile and eventually die, which results initially in a very welcome alleviation of symptoms, and then, eventually cure. 

It’s not clear why Wolbachia are so important to the worm. One theory is that it is to do with iron, or specifically, haem (summarised in Gill et al 2014). Haem is an organic compound with the useful property of sequestering iron, which otherwise can cause severe oxidative stress by combining with hydrogen peroxide to form hydroxyl radicals. Filarial worms cannot produce haem themselves, and although there is some evidence that they can absorb it from their hosts, any produced internally could be very useful, especially in the vulnerable reproductive organs, where in fact, Wolbachia are concentrated. 

Whatever the reason for Wolbachias’ importance, doxycycline is a wonderful example of lateral thinking, and has reduced much suffering. But it has shortcomings. It has to be applied daily for 4 to 6 weeks, which can be very difficult in rural areas, and even then doxycycline is contra indicated for pregnant women and children under 8 years of age as it can interfere with bone and teeth development. 

A recent study by Aljayyoussi et al at the Liverpool School of Tropical Medicine, and the University of Buea in Cameroon, has suggested a more useful alternative. Preclinical trials of the antibiotic rifampicin suggest that it could reduce treatment times to 1-2 weeks, a much more practical proposition than 4-6 weeks, and rifampicin is reportedly safe for pregnant women. There are some caveats. This is a pre-clinical study on mice, who respond differently to rifampicin treatment than humans, and the predicted dose required for humans is high, though reportedly safe in other contexts. Also, rifampicin induces the p-glycoprotein transport system and cytochrome P-450 oxidative enzymes, which can interfere with drug uptake and metabolism, including some drugs used to treat HIV. More generally, large scale application of antibiotics runs the grave risk of resistance development. Rifampicin, for example, is also important in the treatment of tuberculosis, and resistance development in Mycobacterium tuberculosis could have major implications. In this regard, the relatively short proposed treatment time for lymphatic filariasis and onchocerciasis is a bonus.

So, in summary, although lymphatic filariasis and onchocerciasis are still major problems in the world, the use of novel treatments, and adaptation of pre-existing medicines, does offer hope for the future.

 

Community eye health workers in Burundi (Otis Historical Archives National Museum of Health & Medicine).

 

References

Aljayyoussi, G., Tyrer, H.E., Ford, L., Sjoberg, H., Pionnier, N., Waterhouse, D., Davies, J., Gamble,  J., Metugene, H., Cook, D.A., Steven, A., Sharma, R., Guimaraes, A.F., Clare, R.H., Cassidy, A., Johnston, K.L., Myhill, L., Hayward, L., Wanji, S., Turner, J.D., Taylor, M.J., Ward, S.A. (2017). Short-course, high-dose rifampicin achieves Wolbachia depletion predictive of curative outcomes in preclinical models of Lymphatic Filariasis and Onchocerciasis. Sci. Rep., 16, 7(1), 210. http://www.nature.com/articles/s41598-017-00322-5

Gill, A.C., Darby, A.C., Makepeace, B.L. (2014). Iron necessity: the secret of Wolbachia's success? PLoS Negl. Trop. Dis., 16, 8(10), e3224. 

Slatko, B.E., Luck, AN., Dobson, S.L., Foster, J.M. (2014). Wolbachia endosymbionts and human disease control. Mol. Biochem. Parasitol., 195(2), 88-95.