A New Approach to Treatment of Filariasis: Endobacterial Targeting

Abstract & Commentary

Synopsis: In a strategy termed endobacterial targeting, treatment of patients with onchocerciasis with doxycycline sterilized the nematode as a result of inhibition of its endosymbiont rickettsial organism, Wolbachia.

Source: Hoerauf A, et al. Endosymbiotic bacteria in worms as targets for a novel chemotherapy in filariasis. Lancet 2000; 355:1242-1243.

Hoerauf and colleagues in germany randomized Ghanian patients with onchocerciasis to receive either no treatment or doxycycline 100 mg daily for six weeks under daily supervision. Four months post-treatment, onchocercal nodules were excised and examined in a masked fashion. When compared to the nontreatment group, administration of doxycycline was associated with a marked reduction of the number of parasites containing the endosymbiont rickettsia, Wolbachia. Furthermore, in all those containing Wolbachia, their number was also markedly reduced. And, embryogenesis in female worms was uncommon, being found in only nine of 112, compared to 65 of 106 control nematodes (P < 0.0001).

Comment by Stan Deresinski, MD, FACP

Infective third-stage larvae of Onchocerca volvulus are transmitted by the bite of a black fly, developing into the adult stage within subcutaneous nodules of the infected host. The adults may survive for as long as 15 years and the females may produce in excess of 200 microfilariae daily; these, in turn, may each survive for up to two years, during which they migrate and may cause dermatitis, lymphadenopathy, punctate keratitis, chorioretinitis, and other ocular manifestations.

Ivermectin administration is the treatment of choice, but this drug does not effectively kill the long-living adult form of the parasite. Thus, microfilariae reappear several months after treatment with ivermectin as a result of a new cycle of reproduction in the surviving adult worms.

Wolbachia can be detected as endosymbionts in most filarial species, as well as in many arthropods, including up to 20% of insect species.1 They are found, within vacuoles, in all developmental stages of affected filaria and are often present in large numbers in adult worms. Female nematodes are more heavily parasitized than males. In the female, the organisms are present in the reproductive tissues, suggesting vertical transmission via ova cytoplasm.

Members of the Rickettsiacea, Wolbachia are endosymbionts of arthropods, including up to 20% of insect species, as well as nematodes. In the latter, Wolbachia appear to be essential for nematode fertility. Studies of animal filariasis have demonstrated that treatment with tetracycline resulted in degeneration and sterility of adult worms.2,3 The ability to suppress normal embryonic development during the oocyte/morula stages makes this approach of "endobacterial targeting" a potentially effective therapy that may complement or replace the use of ivermectin, a drug that largely leaves the long-living adult form intact. This treatment may also be promising in lymphatic filarial infections.

This approach may have additional benefits. Microfilariae appear to avoid eliciting a host response—until they die. Treatment, in fact, can be associated with a severe systemic inflammatory response. Fortunately, such reactions in response to successful treatment occur less frequently and less intensely after ivermectin therapy than after treatment with diethylcarbamazine, which is no longer recommended in this infection. This systemic reaction after administration of "adulticidal" agents is seen with treatment of other filarial infections as well and has been thought to be the result of a response to the release of proinflammatory products from the dying nematode. However, recent data suggest an alternative explanation—the lipopolysaccharide of Wolbachia may instead be the factor eliciting this response, as well as the inflammatory response in lymph nodes.4 It is thus theoretically possible that eliminating the Wolbachia and its lipopolysaccharide production may prevent the occurrence of inflammatory reactions.

References

1. Bandi C, et al. Phylogeny of Wolbachia in filarial nematodes. Proc R Soc Lond B Biol Sci 1998; 265:2407-2413.

2. Hoerauf A, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. J Clin Invest 1999;103:11-18.

3. Taylor MJ, Hoerauf A. Wolbachia bacteria of filarial nematodes. Parasitol Today 1999;15:437-442.

4. Taylor MJ, et al. Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. J Exp Med 2000;191:1429-1436.

Which of the following is correct?

a. Ivermectin efficiently kills the adult forms of Onchocerca volvulus.

b. Wolbachia are rickettsia that produce lipopolysaccharide.

c. Onchocerciasis is transmitted by mosquito bites.

d. Diethylcarbamazine is the treatment of choice for onchocerciasis.