PMC:1069646 / 2029-11197 JSONTXT

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1 billion people in more than 90 countries are at risk from filarial nematode infections, and 150 million people are infected. The parasitic nematodes are insect-borne and are responsible for lymphatic or cutaneous filariasis, leading to medical conditions including elephantiasis or onchocerciasis (African river blindness). Lymphatic filariasis is caused predominantly by Wuchereria bancrofti and Brugia malayi and affects 120 million individuals, a third of whom show disfigurement, while onchocerciasis, caused by Onchocerca volvulus, affects 18 million people of whom 500,000 have visual impairment and 270,000 are blind [1,2]. Within these filarial parasites are intracellular bacteria that were first observed almost 30 y ago [3,4,5,6].\nThe establishment in 1994 of a Filarial Genome Project funded by the World Health Organization (WHO/Tropical Disease Research/United Nations Development Programme/World Bank) contributed to the rediscovery of these endosymbiotic bacteria. In the analysis of cDNA libraries generated from different life cycle stages of B. malayi, the presence of rare non-Escherichia-coli-like, alpha-proteobacterial sequences implicated the occurrence of endobacterial DNA [7]. Phylogenetic analyses subsequently identified the bacteria as Wolbachia [8]. These endosymbionts have now been found in the vast majority of filarial nematode species, with notable exceptions [3,9,10,11,12,13,14,15,16,17,18,19]. Wolbachia appear to be absent in nonfilarial nematodes [20].\nIn nematodes that contain Wolbachia and which have been well examined, the bacteria are located in the lateral chords (invaginations of the body wall hypodermis that project into the body cavity) in both sexes. They are also localized in oocytes but not in the male reproductive tract. The endosymbionts appear to be present in 100% of individuals within a population, when that species contains them, suggesting that they are required for worm fertility and survival [10,21,22]. They are therefore potential therapeutic targets for filariasis control.\nCertain antialpha proteobacterial agents, most notably tetracycline and doxycycline, but also rifampicin and azithromycin, show inhibitory effects on parasitic nematode development and fertility [13,23,24,25,26,27,28,29,30,31,32,33]. After antibiotic treatment, immunogold staining, using Wolbachia-specific cell-surface probes, shows the absence of Wolbachia in the female reproductive tract and the degeneration of embryos, while Wolbachia remain in the lateral chords, albeit in reduced numbers [34]. Genchi et al. [35] have also shown that Wolbachia are present at 1000X lower frequencies after antibiotic treatment and can still be detected by PCR from female hypodermis tissues, but not from female reproductive tissue. No antibiotic effects are observed in filarial nematodes that do not harbor Wolbachia, nor are they observed with other antibiotics (e.g., penicillin, gentamicin, ciprofloxacin, or erythromycin), suggesting that these effects correlate with Wolbachia presence [11,12,13,36,37]. Human trials using doxycycline, undertaken in Ghana, have shown that this antibiotic interferes with embryogenesis in adult female filariae with a concomitant depletion of Wolbachia from both adults and microfilariae (first stage larvae) of O. volvulus and W. bancrofti [38,39,40,41,42]. Thus, as in animal models, Wolbachia appears to be a therapeutic target for human filarial parasitic infections.\nThe use of anti-Wolbachia chemotherapy against filarial parasites has initiated a novel approach for filarial disease control and eradication. Previous strategies for elimination of filariasis have included vector control in the presence or absence of antiparasitic drugs [43,44,45,46,47]. Diethylcarbamazine, albendazole, and ivermectin have been the most recent drugs of choice for prevention of filarial infections, but they have little effect on adult worms. Thus repeated doses in endemic areas are required to eliminate infections that can arise again within months of treatment [39,44,48]. In addition, the possibility of drug resistance, as observed with intestinal helminths in animals is a concern [49,50,51]. No new therapeutics have been developed in over 20 y, and there is a need for better drugs that permanently sterilize or kill adult worms.\nWolbachia play a role in the host immunological response to filarial parasite invasion. Infection by filarial parasites results in B-cell proliferation and the generation of antibodies directed toward parasite- and Wolbachia-specific antigens, including those to Wolbachia surface protein, heat shock protein, aspartate aminotransferase, and Htr serine protease [11,52,53,54,55,56,57]. Other Wolbachia-specific molecules also play roles in the immune response to filarial infections including the release of stimulatory and modulatory factors from neutrophils and monocytes, which may be related to Wolbachia release upon worm death [58,59,60,61]. One component of the host immune response appears to mimic a lipopolysaccharide (LPS)-like response, typically observed as a host immune response to Gram-negative bacteria (such as the alpha-proteobacterial Wolbachia) [22,58,62,63,64,65]. Further, LPS-like products of Wolbachia appear to be involved in the eye inflammation observed in African river blindness. Leukocytes (neutrophils and eosinophils) infiltrate the cornea as a result of microfilarial invasion and death within the eye, leading to a loss of corneal transparency [66]. LPS-like molecules are implicated in this process due to activation of the toll-like receptor 4 (TLR4) pathway by Wolbachia [61,67].\nRelease of filarial worm-associated molecules, especially after drug treatments that cause worm death in the host, leads to pathogenesis (“Mazzotti Reaction”) [68,69,70,71,72], and Wolbachia has been associated with chronic and acute infection states of filariasis (reviewed in [59]). Repetitive exposures to LPS-like molecules due to release of Wolbachia following death of microfilaria are thought to induce chronic inflammation events giving rise to immune tolerance [65,73], as hyporesponsiveness occurs with increasing parasite load [74,75,76].\nWolbachia endosymbionts can be separated into six supergroups based upon 16S rRNA, Wolbachia surface protein, and ftsZ phylogenetics [8,11,15,77,78,79,80,81,82]. Four supergroups contain Wolbachia from arthropods while supergroup C contains Wolbachia from the nematodes O. volvulus and Dirofilaria immitis, and supergroup D contains Wolbachia from B. malayi, W. bancrofti, and Litomosoides sigmodontis [11,82]. In nematodes, the evolution of Wolbachia parallels the phylogenetics of their hosts, while in the other supergroups, horizontal transmission appears to have occurred [11,14,15,79,82]. The closest bacterial relatives to the Wolbachia are in the Order Rickettsiales, including Rickettsia, Ehrlichia, Cowdria, and Anaplasma, all parasites of mammals that require arthropod vectors for transmission [83,84].\nUp to 70% of all insect species appear to harbor Wolbachia [85,86,87]. While parasitic and maternally inherited in insects, they appear not to be required for host survival. But when present in appropriate genetic backgrounds, they confer developmental effects leading to sex ratio disturbances, feminization of genetic males, parthenogenesis, cytoplasmic incompatibilities and/or reciprocal-cross sterility [79,88,89,90]. It has been suggested that endosymbionts, including Wolbachia, might be of medical importance and used for insect vector control to deliver antiparasitic products to recipient hosts [91,92,93,94,95,96,97,98,99,100,101, 102]. For these reasons, a genome project was initiated and completed on the Wolbachia endosymbiont of Drosophila melanogaster (wMel) [103].\nIdentification of Wolbachia in parasitic nematodes, their role in pathogenesis, their potential as a target for development of antifilarial therapeutics, and their widespread occurrence in arthropods triggered a meeting held in 1999 to initiate a consortium of Wolbachia researchers [104,105]. Three additional meetings have been held (see http://www.wolbachia.sols.uq.edu.au/index.html, and eight additional Wolbachia genomes responsible for diverse phenotypes are being sequenced.\nWe report the second complete genome sequence of Wolbachia and the first from a parasitic nematode, B. malayi (W. pipientis, BruMal TRS strain; Wolbachia endosymbiont of B. malayi [wBm]). We also describe a comparative analysis of reductive evolution in different lineages of endosymbiotic bacteria, a major evolutionary trend in all intracellular parasites and symbionts. Features of the wBm genome are presented as a systematic comparison to wMel and Rickettsia spp., the closest fully sequenced relatives of wBm and more distant intracellular parasites and symbionts of the gamma-proteobacterial lineage, such as Buchnera (aphid endosymbiont), Blochmannia (ant endosymbiont), and Wigglesworthia (tsetse fly endosymbiont) [106,107,108,109,110,111,112]. We also delineate the metabolic pathways that might account for the mutualistic relationship between Wolbachia and its nematode host."}