Over 140 million people are afflicted with filarial nematode-based diseases with over a billion at risk in over 70 countries. Of the estimated 120 million people afflicted with Lymphatic Filariasis, caused by Wuchereria bancrofti, Brugia malayi, and B. timori, 15 million present with swelling of the soft tissue, with the most extreme case known as Elephantiasis, while 25 million men present with scrotal hydrocele, causing great pain and disability. Another 18 million are afflicted with Onchocerciasis, caused by O. volvulus, which results in the deterioration of skin and eye tissue, with River Blindness being the most severe form. Much of the tissue damage is a result of the patient's immune reaction against Wolbachia released from the nematodes. In addition to human suffering, these conditions also result in large economic losses to already poor communities.
In each of these diseases, the afflicted carry the long-lived (5-15 years) adult nematodes (macrofilariae), which in turn produce new generations of microfilaria that are released into the blood stream. Microfilariae are then taken up by blood-sucking insects, where they develop into infective larvae. During the next insect feeding on human blood, the larvae are transmitted to new hosts, where they develop into the next adult generation. Importantly, all current anti-filarial medications are only effective against microfilariae and do not destroy the long-lived adults.
Fortunately, it was recently discovered that all human parasitic filarial nematodes but one require the symbiotic bacteria Wolbachia for fertility and adult viability and this has opened up entirely new avenues for drug development. In addition to Wolbachia's role in the nematode's livelihood, these bacteria have also been found to directly contribute to disease symptoms by triggering the victim's inflammatory immune response. In fact, disease symptoms are frequently aggravated upon medication-induced worm death, due to additional release of Wolbachia from the nematode into the host. Recently, treatment with antibiotics has been shown to increase the efficacy of traditional anthelmintics and to reduce the side effects that are attributed to the release of the symbiotic bacteria.
Despite the biomedical relevance of Wolbachia in filariasis, little is known about the mechanisms of this mutualistic symbiosis. In addition to efforts focused on the development of anti-Wolbachia based therapies, many outstanding questions remain regarding the role of Wolbachia in the filarial immune escape, survival, and fertility. In other words, the interplay between Wolbachia, the filarial nematode, and the mammalian host forming a tripartite system, remains to be better defined.
We will introduce Brugia malayi, a causative agent of human elephantiasis as a model organism, and the technical possibilities and limitations associated with research on filarial nematodes. Using combinations of RNAi and immunofluorescence experiments, our lab is interested in understanding the cell and molecular mechanisms of Wolbachia transmission during the life of Brugia. During embryogenesis, Wolbachia rely on polarity signals to asymetrically segregate into hypodermal precursors. In late larval stages, hypodermal Wolbachia show an ovarian tropism and colonize the female germcells. To better define the basis of the symbiosis, we examined cell defects in Wolbachia-depleted worms. We will report these defects, which include centrosomal and embryonic polarity defects.
