Macrofilaricidal activity of tetracycline against the filarial nematode Onchocerca ochengi : elimination of Wolbachia precedes worm death and suggests a dependent relationship

Abstract

Filarial nematodes are important and widespread parasites of animals and humans. We have been using the African bovine parasite Onchocerca ochengi as a chemotherapeutic model for O. volvulus, the causal organism of`river blindness' in humans, for which there is no safe and e¡ective drug lethal to adult worms. Here we report that the antibiotic, oxytetracycline is macro¢laricidal against O. ochengi. In a controlled trial in Cameroon, all adult worms (as well as micro¢lariae) were killed, and O. ochengi intradermal nodules resolved, by nine months' post-treatment in cattle treated intermittently for six months. Adult worms removed from concurrent controls remained fully viable and reproductively active. By serial electron-microscopic examination, the macro¢laricidal e¡ects were related to the elimination of intracellular micro-organisms, initially abundant. Analysis of a fragment of the 16S rRNA gene from the O. ochengi micro-organisms con¢rmed them to be Wolbachia organisms of the order Rickettsiales, and showed that the sequence di¡ered in only one nucleotide in 858 from the homologous sequence of the Wolbachia organisms of O. volvulus. These data are, to our knowledge, the ¢rst to show that antibiotic therapy can be lethal to adult ¢lariae. They suggest that tetracycline therapy is likely to be macro¢lari-cidal against O. volvulus infections in humans and, since similar Wolbachia organisms occur in a number of other ¢larial nematodes, against those infections too. In that the elimination of Wolbachia preceded the resolution of the ¢larial infections, they suggest that in O. ochengi at least, the Wolbachia organisms play an essential role in the biology and metabolism of the ¢larial worm.

Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM

“…It is closely related to the human pathogen O. volvulus on the basis of 16S ribosomal RNA analyses (18) and shares the same vector, Simulium damnosum (63)(64)(65)(66). Wolbachia bacteria belonging to two distinct phylogenetic clades, those that are endosymbionts of the filarial nematode O. ochengi and those from a mosquito cell line Aedes albopictus, induced remarkably similar innate immune receptors and intracellular signaling pathways.…”

“…In filarial worms, Wolbachia bacteria are concentrated in intracytoplasmic vacuoles of hypodermal lateral cords and female reproductive organs and are also detectable in oocytes and microfilaria, reflecting matrilinear inheritance (16). Nematode reproduction, molting, and survival dependent on the endosymbiont as prolonged exposure to antibiotics targeting Wolbachia result in decreased fecundity, impaired molting, and even worm death in vitro as well as in animal and human infections (17)(18)(19)(20). Results of studies of filaria-infected individuals are consistent with the hypothesis that Wolbachia contribute to the pathogenesis of filarial disease.…”

Evolutionary origin of insect– Wolbachia nutritional mutualism

“…Previous antibiotic curing experiments showed that the Wolbachia strains wBm, wOo, and wCle are essential for their hosts B. malayi, O. ochengi, and C. lectularius, respectively (9,26,27). Although wCle was shown to provide B vitamins to its bedbug host (Fig.…”

Fitness advantage and cytoplasmic incompatibility in Wolbachia single- and superinfected Aedes albopictus

“…The success of Wolbachia can be attributed in large part to its ability to manipulate the reproduction of its host to promote infection spread into the host population. Wolbachia infections provide multiple examples of mechanisms that promote infection spread, ranging along the continuum from mutualism (Hoerauf et al, 1999;Langworthy et al, 2000) to reproductive parasitism. Examples of the latter include cytoplasmic incompatibility (Hoffmann and Turelli, 1997), male killing (Hurst et al, 1999), parthenogenesis (Stouthamer et al, 1993), and feminization (Rousset et al, 1992).…”