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Year : 2019  |  Volume : 149  |  Issue : 6  |  Page : 706-714

Anti-Wolbachia therapy for onchocerciasis & lymphatic filariasis: Current perspectives

1 Department of Medicine, Faculty of Medicine & Health Sciences; Laboratory of Medical Gerontology, Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia
2 Liverpool Brain Infection Group, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
3 Department of Surgery, Faculty of Medicine & Health Sciences; Laboratory of Medical Gerontology, Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia
4 Laboratory of Medical Gerontology, Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia
5 Department of Family Medicine, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
6 Department of Medicine, Faculty of Medicine & Health Sciences, Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia

Date of Submission15-Mar-2017
Date of Web Publication3-Sep-2019

Correspondence Address:
Dr Wan Aliaa Wan Sulaiman
Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmr.IJMR_454_17

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Onchocerciasis and lymphatic filariasis (LF) are human filarial diseases belonging to the group of neglected tropical diseases, leading to permanent and long-term disability in infected individuals in the endemic countries such as Africa and India. Microfilaricidal drugs such as ivermectin and albendazole have been used as the standard therapy in filariasis, although their efficacy in eliminating the diseases is not fully established. Anti-Wolbachia therapy employs antibiotics and is a promising approach showing potent macrofilaricidal activity and also prevents embryogenesis. This has translated to clinical benefits resulting in successful eradication of microfilarial burden, thus averting the risk of adverse events from target species as well as those due to co-infection with loiasis. Doxycycline shows potential as an anti-Wolbachia treatment, leading to the death of adult parasitic worms. It is readily available, cheap and safe to use in adult non-pregnant patients. Besides doxycycline, several other potential antibiotics are also being investigated for the treatment of LF and onchocerciasis. This review aims to discuss and summarise recent developments in the use of anti-Wolbachia drugs to treat onchocerciasis and LF.

Keywords: Black flies - doxycycline - filariasis - lymphatic filariasis - macrofilaricides - minocycline onchocerciasis - Wolbachia

How to cite this article:
Wan Sulaiman WA, Kamtchum-Tatuene J, Mohamed MH, Ramachandran V, Ching SM, Sazlly Lim SM, Hashim HZ, Inche Mat LN, Hoo FK, Basri H. Anti-Wolbachia therapy for onchocerciasis & lymphatic filariasis: Current perspectives. Indian J Med Res 2019;149:706-14

How to cite this URL:
Wan Sulaiman WA, Kamtchum-Tatuene J, Mohamed MH, Ramachandran V, Ching SM, Sazlly Lim SM, Hashim HZ, Inche Mat LN, Hoo FK, Basri H. Anti-Wolbachia therapy for onchocerciasis & lymphatic filariasis: Current perspectives. Indian J Med Res [serial online] 2019 [cited 2021 Sep 16];149:706-14. Available from:

   Introduction Top

Onchocerciasis (also known as river blindness disease) and lymphatic filariasis (LF) are human filarial diseases caused by parasitic worms. These cause a major health burden mainly in African and Indian subcontinent with small foci in southern and central America[1]. Onchocerca volvulus, the filarial nematode species that causes onchocerciasis, is transmitted to humans via infected Simulium (black flies) bites. Patients with onchocerciasis exhibit skin lesions but in advanced untreated cases, the infection may lead to loss of vision due to the inflammatory response towards microfilariae in the eye[2]. LF caused by Wuchereria bancro⎰ti, Brugia malayi and B. timori are transmitted to humans through mosquito bites. In patients with LF, lymphatic complications such as elephantiasis, hydrocoele and lymphoedema cause significant morbidity[3].

To date, the treatment and control of onchocerciasis and LF depend on microfilaricides such as ivermectin and albendazole. Given under mass drug administration (MDA) programme to all adults (except pregnant women) and children >15 kg either once or twice a year, it is effective for decreasing microfilarial load, but are of limited potential against microfilariae. As a result, continuous delivery for at least 15-17 yr is required to break the transmission cycle[1],[4]. The issue of resistance to these drugs has also been raised as persistent microfilaridermias despite multiple treatments of ivermectin observed among patients in a few endemic areas of onchocerciasis[5],[6]. Consequently, the transmission of the filarial nematode is not interrupted, since children in the MDA area still have microfilariae in their skin or blood.

Because of the disadvantages of the current standard therapy for onchocerciasis and LF, the search for new potential treatment targets continues. Chemotherapeutic agents targeting Wolbachia, a bacterial endosymbiont present in the nematodes causing onchocerciasis and LF, have been extensively studied[7], and are discussed in this review.

   Wolbachia : A bacterial endosymbiont Top

Wolbachia is an endosymbiont bacteria found in numerous arthropod species, first identified by Hertig and Wolbach in 1924 in the mosquito Culex pipiens[8]. It is a Gram-negative α-proteobacteria, a member of the Rickettsiales order[9]. Many filarial nematodes are recognized as host to Wolbachia[10], except a few species such as Loa loa, Acanthocheilonema viteae, Onchocerca flexuosa and Setaria equina[11],[12]. The main species for LF and onchocerciasis such as Wuchereria bancrofti, B. malayi and O. volvulus were also found to contain an intracellular bacterium which showed similarities with Wolbachia according to DNA sequencing data[13]. Moreover, filarial nematodes are found to be infected with Wolbachia at all stages of their life cycles[14].

An important mutualistic symbiosis exists between Wolbachia and their nematode hosts. This interaction has contributed to their survival. Wolbachia is necessary for growth, fertility and viability of the nematode host, while the host supplies amino acids needed for Wolbachia's development[15]. Furthermore, Wolbachia is transmitted vertically via oocytes in the filarial worms[14]. Therefore, sterilization of the worms will decrease the presence of the intracellular endosymbiont. Without Wolbachia, the viability of the filarial worms will be affected[16]. All these features make Wolbachia an interesting target for filarial drug treatment[1].

   Role of Wolbachia in the pathogenesis of filariasis Top

The knowledge on the role of Wolbachia in the pathogenesis of human filarial infections is mostly derived from studies of the molecular pathogenesis of inflammation triggered by filarial nematodes[17]. The involvement of Wolbachia from the acute phase of infection to the development of chronic complications includes the induction of pro-inflammatory and immunomodulatory mechanisms in the host[17]. The release of Wolbachia lipoprotein could cause activation of innate inflammatory responses as well as Th1-adaptive immune responses[18]. The degranulation of eosinophils needed for filarial eradication is inhibited by Wolbachia, resulting in an incompetent neutrophil response of the host[19]. This manipulation of the local inflammatory response by Wolbachia provides longevity to the host through a defensive mutualism by conferring immunity against the lethal effector cell response[19].

The disease manifestations are correlated with both circulating Wolbachia-related antigen and antibodies. The presence of circulating Wolbachia antigens might result from the natural excretion of Wolbachia products by the nematodes or the release of these products from the dying worms[20],[21]. Initially, it was thought that the development of pathology seen in filarial diseases occurred as a result of the immune response alone. However, a study[22] has shown that O. volvulus does not induce corneal inflammation when depleted of Wolbachia using antibiotics[22]. Thus, the presence of Wolbachia was also implicated in the pathogenesis of O. volvulus keratitis. In an experimental study, soluble extract of O. volvulus containing Wolbachia was injected into the corneal stroma of mice. The study showed that Wolbachia led to the Toll-like receptors (TLR)-2 activation in macrophages and local stromal cells resulting in the production of pro-inflammatory cytokines[23]. Expressed in the cornea tissues, TLR are endosomal and surface receptors that respond to the bacterial antigen[24]. Subsequently, neutrophil-mediated corneal inflammation ensues while repeated infections will exacerbate the inflammatory response causing permanent corneal destruction[25]. As a result, the visual acuity will be affected, and chronically infected patients will become blind[26].

Similarly, in LF, Wolbachia has also been implicated in the pathogenesis of the disease. Production of lymphangiogenic factors such as angiopoietin-1 and vascular endothelial growth factor is triggered by activation of TLR-2 by extracts of B. malayi[27]. High levels of these lymphangiogenic factors are associated with the severity of the disease[27],[28]. On the contrary, depletion of Wolbachia in patients infected with W. Bancrofti using doxycycline caused an improvement in symptoms as shown by a reduction of the dilatation of the scrotal lymphatic vessels[29].

   Anti-Wolbachia therapy Top

Overview: Current filariasis treatment and public health control programmes depend on the utilization of microfilaricides which target the microfilariae instead of the adult worms[3]. In the MDA programmes led by the WHO, albendazole combined with either ivermectin or diethylcarbamazine are given as treatment of LF[3], while only ivermectin is given for onchocerciasis in all endemic areas[2]. Although these microfilaricidal drugs have been shown to reduce the number of cases, the disadvantage lies in the long duration of treatment; approximately 17 years for onchocerciasis[1] and five years for LF[1]. As the adult worms also have a long lifespan, any disruption of the anti-microfilariae treatment process will hamper the prevention of transmission[1]. The emergence of resistance to ivermectin in some endemic regions represents an issue of concern[6].

Initial pre-clinical studies demonstrated that antibiotic therapy targeting the endosymbiont bacteria could cause embryotoxicity, developmental retardation and death of adult filarial nematodes[30],[31]. It is known that anti-Wolbachia therapy has potent macrofilaricidal activity and also prevents embryogenesis resulting in successful eradication of microfilarial burden, thus averting the risk of adverse events resulting from the destruction of the targeted parasite or the co-infection with L. loa[1]. How the antibiotics affected Wolbachia was not fully understood until a transcriptomic and proteomic study demonstrated that there were genome-wide responses of Wolbachia to doxycycline causing impairment of the bacterial metabolism[32]. The subsequent depletion of Wolbachia causes significant apoptosis of both the adult germline and the somatic cells in the embryos and microfilariae that leads to sterilization of the filarial nematodes[16]. From these observations, Wolbachia appeared to be the right target for the treatment of human filarial diseases[33].

Since the first human clinical trial showing the effectiveness of doxycycline in eradicating Wolbachia and leading to the death of adult worms[33], doxycycline has been established as an effective anti-Wolbachia treatment with good macrofilaricidal activity[28],[34]. Doxycycline is readily available, cheap and safe to use in adults patients. Though macrofilaricidal drugs (like doxycycline) have been shown to be effective[35], several factors have restrained their use in the public MDA programmes.

The anti-Wolbachia consortium (A-WOL) was founded in 2007 with the objective to identify new anti-Wolbachia drugs that are safe to the contraindicated groups and could be administered on a large scale with a shorter course of treatment[36]. From a total of 2773 compounds screened from the registered drugs, 121 had anti-Wolbachia activity wherein only four compounds were orally available and superior to doxycycline with minocycline showing the greatest potential[37].

Doxycycline: The first human trial of anti-Wolbachia drugs was done by Hoerauf et al[33] in Ghana. In this prospective trial to investigate the effectiveness of targeting Wolbachia in human onchocerciasis, doxycycline was administered at 100 mg daily dose for six weeks. One of the outcomes was the depletion of more than 80 per cent Wolbachia four months after the treatment. Furthermore, the embryogenesis of the treated worms was interrupted and viability affected compared to the non-treated worms. In the subsequent extension of the study[38], the patients who received doxycycline and ivermectin were compared with patients who had received ivermectin alone. When examined after 19 months, amicrofilaridermia was observed in th e doxycycline and ivermectin group, suggesting that doxycycline significantly enhances the microfilaricidal effect of ivermectin. This study established that the worm sterilization was long term, up to 1.5 years after treatment and was probably irreversible[38].

Besides the synergistic microfilaricidal effect with ivermectin, macrofilaricidal effect as well as sterilization of the female Onchocerca worms after a course of doxycycline treatment was also discovered. Hoerauf et al[39], in their double-blind randomized placebo-controlled trial in Ghana, showed that a six-week course of doxycycline had a higher macrofilaricidal effect of up to 60 per cent, as compared to 50 per cent for the shorter four-week course. Furthermore, the residual live female worms analyzed from the onchocercomata nodules were sterile. A similar randomized controlled study in Cameroon[40] and another open study by Hoerauf et al[41] using doxycycline at 100 mg/day for five weeks confirmed that both macrofilaricidal and embryotoxic activities were attributable to the monotherapy with doxycycline without administration of ivermectin. A good safety profile was observed as no serious adverse events were reported from the doxycycline-treated group. Besides, the utilization of antibiotics in areas of co-endemicity with loiasis is shown to be safe and effective for onchocerciasis[40].

A Cochrane systematic review analyzed three randomized controlled trials comparing the treatment of doxycycline added to ivermectin versus ivermectin only on 466 onchocerciasis patients in West Africa[42]. In the two previous studies mentioned[39],[40], microfilarial loads in skin snips were quantified. The results showed sustained effects of six-week doxycycline treatment of Wolbachia depletion, microfilaricidal and macrofilaricidal as well as sterilization effect for up to two years[39],[40]. In the study that measured visual outcomes at six-month follow up, they found that although the onchocerciasis clinical symptoms improved, no significant visual improvement was found among the patients treated with doxycycline plus ivermectin when compared to those who received ivermectin alone[43]. Better designed trials of doxycycline with standardized clinical outcomes such as the efficacy of the interventions in preventing visual acuity and visual field loss would provide more condusive evidence.

Doxycycline has also demonstrated its efficacy as anti-Wolbachia therapy to reduce the burden of LF. In a randomized clinical study, doxycycline therapy for three weeks significantly reduced the microfilarial load and was more effective in inducing a microfilaraemia for up to two years when compared to monotherapy with either albendazole or ivermectin[44]. The severity of lymphoedema also improved after treatment with doxycycline[45]. These results were translated into the use of doxycycline to improve clinical symptoms. In another randomized controlled trial which compared doxycycline with amoxicillin on patients with and without active LF infection, though significant improvement of the severity of lymphoedema was noted for both drugs at one and two years of follow up, higher progression of disease was observed in 29 per cent of patients in the amoxicillin group and 56 per cent of patients in the placebo group, compared to a lower five per cent in the doxycycline arm[27]. The treatment time of LF with doxycycline is also shorter compared to that in onchocerciasis[37], possibly due to the presence of the filarial nematodes in the lymphatic vessels rather than the skin where drug penetration is more difficult. Taking into account the benefits shown even in patients without active infection and the fact that the efficacy of albendazole or ivermectin as microfilaricides is still undetermined for LF[46], the addition of doxycycline as part of the standard treatment for LF should be considered.

Regarding the treatment duration, intermittent short multiple courses over a longer period are found to be better than a continuous intensive once-off shorter duration course[47],[48],[49]. For example, an in vivo study using O. ochengi in cattle discovered a significant post-treatment macrofilaricidal activity in the group receiving intermittent antibiotics (20 mg/kg monthly for 6 months) compared to a continuous course (10 mg/kg daily for 2 wk)[47]. This superiority of the prolonged intermittent regimen was explained by the findings from an in vitro study using the Wolbachia-infected Aedes albopictus mosquito, which showed that significant Wolbachia depletion occurred after antibiotics withdrawal[48]. A later animal study also proved that a six-month regimen of oxytetracycline with once a month administration was more efficacious than a shorter but continuous course, either at three or six weeks duration[49].

Although doxycycline is the best available treatment for onchocerciasis or LF in patients attending clinical settings, there are barriers that restricted doxycycline usage in the public health MDA programmes[1]. A study done in Cameroon showed that by the end of six weeks, successful adherence was achieved in 97.5 per cent of the 13,000 community members who started the treatment at the health district levels[50]. The cost of the six-week doxycycline treatment was found to be US$ 2.77 which was relatively economical compared to a single dose of ivermectin at US$ 1.77[51]. This has proved that a large-scale distribution of doxycycline for the treatment of filariasis using a community-directed approach is feasible and economical. Evidence from a meta-analytical modelling framework suggests that a shorter course of four-week doxycycline is sufficient for an effective anti-Wolbachia therapy, enabling a better compliance[35].

Doxycycline resistance in filariasis has not been reported. In general, the risk of drug resistance with doxycycline is much lower compared to penicillin or fluoroquinolones[52],[53]. However, another limitation of doxycycline usage is its contraindication in pregnancy and in case of young children remains unresolved. The main mechanism of action of this antibiotic from the tetracycline class is on the inhibition of the bacterial RNA polymerases (RNAPs) and protein synthesis[54]. Hence, in the foetus and young children, doxycycline has the potential to bind to calcium in the developing bones and teeth, thus forming deposits and/or resulting in dental staining and hypoplasia[54]. This disadvantage motivated an active search for other potential anti-Wolbachia treatment for filariasis. Because of the potential shown in earlier studies and better safety profile, rifampicin, azithromycin and minocycline have also been assessed in clinical trials as anti-Wolbachia chemotherapy[55],[56].

Azithromycin: The initial in vitro study assessing the effect of azithromycin on B. malayi resulted in a partial inhibition of molting of the parasite[57]. This was not reflected in the subsequent clinical trial of six-week azithromycin monotherapy administered at either 250 mg/day or 1.2 g/per week. The treatment showed no significant reduction of the worm load after 12 months[58]. In another open-label randomized study in Guatemala[59], onchocerciasis patients were given either rifampicin or azithromycin or both drugs for a short course of five days. Neither Wolbachia depletion nor anti-filarial effects were observed in either group. These studies confirmed the futility of azithromycin in the treatment of human filariasis.

Rifampicin: Rifampicin is a broad-spectrum antibiotic that is safe for children and pregnant women[60]. However, it had a false start when an animal study showed insignificant results with rifampicin. In the study, O. Ochengi infected cattle were treated with either rifampicin alone or in combination with oxytetracycline for three weeks. Both regimens proved to cause no significant macrofilaricidal or macrofilaricidal effect as compared to oxytetracycline monotherapy[49]. This negative result may be explained by the small sample size which was only six cattle for each group. On the other hand, a human study of rifampicin[61] showed positive results. Rifampicin monotherapy was given to 26 onchocerciasis patients for two or four weeks. The study showed significant reduction of Wolbachia at 18 months post-treatment compared to the untreated group, with a higher proportion of reduction observed in the four-week rifampicin regimen[61]. Later on, a preclinical study proved a synergistic effect between albendazole and rifampicin that significantly shortened the treatment duration[62]. After treatment with a seven-day combination of albendazole and rifampicin, Wolbachia was almost totally eradicated, and as a result, the macrofilaricidal effect was fast.

The potential use of rifampicin in filariasis may be limited by its role as the backbone treatment for tuberculosis, since a widespread use of rifampicin poses a substantial risk of cross-resistance with Mycobacterium spp[63]. To minimize this risk, a study tested a short course (1-2 wk), high dose rifampicin (35 mg/kg) in preclinical onchocerciasis and LF mouse models and it accelerated the treatment effect on both filarial diseases[64]. Since rifampicin had the advantage of safer use in children and during pregnancy compared to doxycycline, this regimen should be further investigated in clinical trials to determine its safety and clinical efficacy as well as the suitability to be utilized in a MDA programme.

Minocycline: Minocycline is a semi-synthetic tetracycline which is bacteriostatic on a wide range of bacterial species[65]. In the A-WOL cell culture screening assay, minocycline was identified as the most potent compound[37] more effective than doxycycline and rifampicin in an initial in vitro screen[66]. In a LF murine infection model, a 28-day treatment of minocycline with a dosage of 25 mg/kg twice daily resulted in a greater reduction of Wolbachia than obtained with doxycycline (99.51 vs. 90.35%) with a higher rate of worm sterilization[67]. In a pilot randomized, open-label, clinical trial in Ghana, a three-week course of minocycline resulted in 73 per cent depletion of Wolbachia compared to 64 per cent with a three-week course of doxycycline[68]. This suggested that minocycline was more potent than doxycycline and more randomized controlled trials will be needed to further validate minocycline efficacy. Although minocycline is a potent and well-tolerated antibiotic without severe adverse events[68], it is also contraindicated for children and pregnant women.

Corallopyronin A: Corallopyronin A, originally isolated from the myxobacterial strain Corallococcus coralloides, is a natural compound and a non-competitive RNAP inhibitor[69]. It has many bioactivities including microfilarial activity. The genome of Wolbachia found in filarial nematodes encodes a complete RNAP which is a suitable target for the antibiotic. In vitro and in vivo studies in an animal model have shown the potential of corallopyronin A against Wolbachia with a good safety profile[70],[71]. However further clinical trials will be required to examine the efficacy of corallopyronin as a treatment regimen in patients with onchocerciasis and LF.

Other anti-Wolbachia therapy: Other potential antibiotics that have progressed into clinical trials are moxifloxacin and rifapentine. Both of these antibiotics are currently investigated in phase 2 randomized open-label clinical trials, with the following dosages: rifapentine 900 mg/day plus moxifloxacin 400 mg/day for 14 or for seven days[72]. Previous in vitro and in vivo experiments using moxifloxacin and rifapentine showed that this combination administered for only 4-7 days also significantly depleted Wolbachia load in adult worms[73].

Berberine[74], rapamycin[75], globomycin[76] and succinyl acetone[77] are currently in the initial phase of experimental research. The current anti-infective compounds being used as anti-Wolbachia treatment are summarized in the [Table 1]. Besides antibiotics, several non-antimicrobial compounds such as anti-oxidants and anti-histamines have demonstrated activity against Wolbachia in vitro which opens up other potential anti-Wolbachia therapeutic combinations to be explored and exploited in future research[73].
Table 1: Summary of anti-Wolbachia chemotherapeutic agents

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   Conclusion Top

Despite doxycycline being the best available treatment for onchocerciasis and there are barriers in its usage and implementation in the public health MDA programmes. Drug adherence, toxicity, resistance, and financial cost will have to be taken into consideration before the final decision is made by health authorities. Meanwhile, other potential alternatives for depleting Wolbachia in adult filarial worms may be identified within the A-WOL Consortium product portfolio. Also more clinical trials will have to be carried out to determine their efficacy and suggest better strategies to manage onchocerciasis and LF in the future.

Financial support & sponsorship: Authors acknowledge the Universiti Putra Malaysia for providing financial support (grant no. GP-Berimpak/2017/9585500).

Conflicts of Interest: None.

   References Top

Taylor MJ, Hoerauf A, Bockarie M. Lymphatic filariasis and onchocerciasis. Lancet 2010; 376 : 1175-85.  Back to cited text no. 1
World Health Organization. WHO | Onchocerciasis. Fact Sheet. WHO; 2016. Available from:, accessed on May 18, 2016.  Back to cited text no. 2
World Health Organization. WHO | Lymphatic Filariasis. Fact Sheet. World Health Organization; 2016. Available from:, accessed on May 18, 2016.  Back to cited text no. 3
Diawara L, Traoré MO, Badji A, Bissan Y, Doumbia K, Goita SF, et al. Feasibility of onchocerciasis elimination with ivermectin treatment in endemic foci in Africa:First evidence from studies in Mali and Senegal. PLoS Negl Trop Dis 2009; 3 : E497.  Back to cited text no. 4
Awadzi K, Boakye DA, Edwards G, Opoku NO, Attah SK, Osei-Atweneboana MY, et al. An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Ann Trop Med Parasitol 2004; 98 : 231-49.  Back to cited text no. 5
Osei-Atweneboana MY, Awadzi K, Attah SK, Boakye DA, Gyapong JO, Prichard RK, et al. Phenotypic evidence of emerging ivermectin resistance in Onchocerca volvulus. PLoS Negl Trop Dis 2011; 5 : E998.  Back to cited text no. 6
Hoerauf A. New strategies to combat filariasis. Expert Rev Anti Infect Ther 2006; 4 : 211-22.  Back to cited text no. 7
Hertig M, Wolbach SB. Studies on rickettsia-like micro-organisms in insects. J Med Res 1924; 44 : 329-74.7.  Back to cited text no. 8
Williams KP, Sobral BW, Dickerman AW. A robust species tree for the alphaproteobacteria. J Bacteriol 2007; 189 : 4578-86.  Back to cited text no. 9
Casiraghi M, Bain O, Guerrero R, Martin C, Pocacqua V, Gardner SL, et al. Mapping the presence of Wolbachia pipientis on the phylogeny of filarial nematodes: Evidence for symbiont loss during evolution. Int J Parasitol 2004; 34 : 191-203.  Back to cited text no. 10
McGarry HF, Pfarr K, Egerton G, Hoerauf A, Akue JP, Enyong P, et al. Evidence against Wolbachia symbiosis in Loa loa. Filaria J 2003; 2 : 9.  Back to cited text no. 11
Chirgwin SR, Porthouse KH, Nowling JM, Klei TR. The filarial endosymbiont Wolbachia sp. is absent from Setariaequina. J Parasitol 2002; 88 : 1248-50.  Back to cited text no. 12
Sironi M, Bandi C, Sacchi L, Di Sacco B, Damiani G, Genchi C, et al. Molecular evidence for a close relative of the arthropod endosymbiont Wolbachia in a filarial worm. Mol Biochem Parasitol 1995; 74 : 223-7.  Back to cited text no. 13
Taylor MJ, Bilo K, Cross HF, Archer JP, Underwood AP. 16S rDNA phylogeny and ultrastructural characterization of Wolbachia intracellular bacteria of the filarial nematodes Brugia malayi, B. pahangi, and Wuchereria bancrofti. Exp Parasitol 1999; 91 : 356-61.  Back to cited text no. 14
Foster J, Ganatra M, Kamal I, Ware J, Makarova K, Ivanova N, et al. The Wolbachia genome of Brugia malayi: Endosymbiont evolution within a human pathogenic nematode. PLoS Biol 2005; 3 : E121.  Back to cited text no. 15
Landmann F, Voronin D, Sullivan W, Taylor MJ. Anti-filarial activity of antibiotic therapy is due to extensive apoptosis after Wolbachia depletion from filarial nematodes. PLoS Pathog 2011; 7 : E1002351.  Back to cited text no. 16
Brattig NW, Rathjens U, Ernst M, Geisinger F, Renz A, Tischendorf FW, et al. Lipopolysaccharide-like molecules derived from Wolbachia endobacteria of the filarial Onchocerca volvulus are candidate mediators in the sequence of inflammatory and antiinflammatory responses of human monocytes. Microbes Infect 2000; 2 : 1147-57.  Back to cited text no. 17
Turner JD, Langley RS, Johnston KL, Gentil K, Ford L, Wu B, et al. Wolbachia lipoprotein stimulates innate and adaptive immunity through toll-like receptors 2 and 6 to induce disease manifestations of filariasis. J Biol Chem 2009; 284 : 22364-78.  Back to cited text no. 18
Hansen RDE, Trees AJ, Bah GS, Hetzel U, Martin C, Bain O, et al. A worm's best friend: Recruitment of neutrophils by Wolbachia confounds eosinophil degranulation against the filarial nematode Onchocerca ochengi. Proc Biol Sci 2011; 278 : 2293-302.  Back to cited text no. 19
Shiny C, Krushna NSA, Archana B, Farzana B, Narayanan RB. Serum antibody responses to Wolbachia surface protein in patients with human lymphatic filariasis. Microbiol Immunol 2009; 53 : 685-93.  Back to cited text no. 20
Anuradha R, George PJ, Pavan Kumar N, Fay MP, Kumaraswami V, Nutman TB, et al. Circulating microbial products and acute phase proteins as markers of pathogenesis in lymphatic filarial disease. PLoS Pathog 2012; 8 : E1002749.  Back to cited text no. 21
Brattig NW, Büttner DW, Hoerauf A. Neutrophil accumulation around Onchocerca worms and chemotaxis of neutrophils are dependent on Wolbachia endobacteria. Microbes Infect 2001; 3 : 439-46.  Back to cited text no. 22
Gillette-Ferguson I, Daehnel K, Hise AG, Sun Y, Carlson E, Diaconu E, et al. Toll-like receptor 2 regulates CXC chemokine production and neutrophil recruitment to the cornea in Onchocerca volvulus/Wolbachia-induced keratitis. Infect Immun 2007; 75 : 5908-15.  Back to cited text no. 23
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors. Nat Immunol 2010; 11 : 373-84.  Back to cited text no. 24
Gentil K, Pearlman E. Gamma interferon and interleukin-1 receptor 1 regulate neutrophil recruitment to the corneal stroma in a murine model of Onchocerca volvulus keratitis. Infect Immun 2009; 77 : 1606-12.  Back to cited text no. 25
Tamarozzi F, Halliday A, Gentil K, Hoerauf A, Pearlman E, Taylor MJ, et al. Onchocerciasis: The role of Wolbachia bacterial endosymbionts in parasite biology, disease pathogenesis, and treatment. Clin Microbiol Rev 2011; 24 : 459-68.  Back to cited text no. 26
Hoerauf A, Mand S, Fischer K, Kruppa T, Marfo-Debrekyei Y, Debrah AY, et al. Doxycycline as a novel strategy against bancroftian filariasis-depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production. Med Microbiol Immunol 2003; 192 : 211-6.  Back to cited text no. 27
Mand S, Debrah AY, Klarmann U, Batsa L, Marfo-Debrekyei Y, Kwarteng A, et al. Doxycycline improves filarial lymphedema independent of active filarial infection: A randomized controlled trial. Clin Infect Dis 2012; 55 : 621-30.  Back to cited text no. 28
Mand S, Pfarr K, Sahoo PK, Satapathy AK, Specht S, Klarmann U, et al. Macrofilaricidal activity and amelioration of lymphatic pathology in bancroftian filariasis after 3 weeks of doxycycline followed by single-dose diethylcarbamazine. Am J Trop Med Hyg 2009; 81 : 702-11.  Back to cited text no. 29
Chirgwin SR, Coleman SU, Porthouse KH, Nowling JM, Punkosdy GA, Klei TR, et al. Removal of Wolbachia from Brugia pahangi is closely linked to worm death and fecundity but does not result in altered lymphatic lesion formation in Mongolian gerbils (Meriones unguiculatus). Infect Immun 2003; 71 : 6986-94.  Back to cited text no. 30
Hoerauf A, Nissen-Pähle K, Schmetz C, Henkle-Dührsen K, Blaxter ML, Büttner DW, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. J Clin Invest 1999; 103 : 11-8.  Back to cited text no. 31
Darby AC, Gill AC, Armstrong SD, Hartley CS, Xia D, Wastling JM, et al. Integrated transcriptomic and proteomic analysis of the global response of Wolbachia to doxycycline-induced stress. ISME J 2014; 8 : 925-37.  Back to cited text no. 32
Hoerauf A, Volkmann L, Hamelmann C, Adjei O, Autenrieth IB, Fleischer B, et al. Endosymbiotic bacteria in worms as targets for a novel chemotherapy in filariasis. Lancet 2000; 355 : 1242-3.  Back to cited text no. 33
Taylor MJ, Makunde WH, McGarry HF, Turner JD, Mand S, Hoerauf A, et al. Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: A double-blind, randomised placebo-controlled trial. Lancet 2005; 365 : 2116-21.  Back to cited text no. 34
Walker M, Specht S, Churcher TS, Hoerauf A, Taylor MJ, Basáñez MG, et al. Therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness. Clin Infect Dis 2015; 60 : 1199-207.  Back to cited text no. 35
A-WOL. A-WOL | Anti Wolbachia Consortium; 2016. Available from:, accessed on May 23, 2016.  Back to cited text no. 36
Taylor MJ, Hoerauf A, Townson S, Slatko BE, Ward SA. Anti-Wolbachia drug discovery and development: Safe macrofilaricides for onchocerciasis and lymphatic filariasis. Parasitology 2014; 141 : 119-27.  Back to cited text no. 37
Hoerauf A, Mand S, Adjei O, Fleischer B, Büttner DW. Depletion of Wolbachia endobacteria in Onchocerca volvulus by doxycycline and microfilaridermia after ivermectin treatment. Lancet 2001; 357 : 1415-6.  Back to cited text no. 38
Hoerauf A, Specht S, Büttner M, Pfarr K, Mand S, Fimmers R, et al. Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: A randomized placebo-controlled study. Med Microbiol Immunol 2008; 197 : 295-311.  Back to cited text no. 39
Turner JD, Tendongfor N, Esum M, Johnston KL, Langley RS, Ford L, et al. Macrofilaricidal activity after doxycycline only treatment of Onchocerca volvulus in an area of Loa loa co-endemicity: A randomized controlled trial. PLoS Negl Trop Dis 2010; 4 : e660.  Back to cited text no. 40
Hoerauf A, Specht S, Marfo-Debrekyei Y, Büttner M, Debrah AY, Mand S, et al. Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus. Parasitol Res 2009; 104 : 437-47.  Back to cited text no. 41
Abegunde AT, Ahuja RM, Okafor NJ. Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis. Cochrane Database Syst Rev 2016; CD011146.  Back to cited text no. 42
Masud H, Qureshi TQ, Dukley M. Effects of ivermectin with and without doxycycline on clinical symptoms of onchocerciasis. J Coll Physicians Surg Pak 2009; 19 : 34-8.  Back to cited text no. 43
Turner JD, Mand S, Debrah AY, Muehlfeld J, Pfarr K, McGarry HF, et al. A randomized, double-blind clinical trial of a 3-week course of doxycycline plus albendazole and ivermectin for the treatment of Wuchereria bancrofti infection. Clin Infect Dis 2006; 42 : 1081-9.  Back to cited text no. 44
Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, et al. Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog 2006; 2 : e92.  Back to cited text no. 45
Critchley J, Addiss D, Gamble C, Garner P, Gelband H, Ejere H, et al. Albendazole for lymphatic filariasis. Cochrane Database Syst Rev 2005; CD003753.  Back to cited text no. 46
Gilbert J, Nfon CK, Makepeace BL, Njongmeta LM, Hastings IM, Pfarr KM, et al. Antibiotic chemotherapy of onchocerciasis: In a bovine model, killing of adult parasites requires a sustained depletion of endosymbiotic bacteria (Wolbachia species). J Infect Dis 2005; 192 : 1483-93.  Back to cited text no. 47
Makepeace BL, Rodgers L, Trees AJ. Rate of elimination of Wolbachia pipientis by doxycycline in vitro increases following drug withdrawal. Antimicrob Agents Chemother 2006; 50 : 922-7.  Back to cited text no. 48
Bah GS, Ward EL, Srivastava A, Trees AJ, Tanya VN, Makepeace BL, et al. Efficacy of three-week oxytetracycline or rifampin monotherapy compared with a combination regimen against the filarial nematode Onchocerca ochengi. Antimicrob Agents Chemother 2014; 58 : 801-10.  Back to cited text no. 49
Wanji S, Tendongfor N, Nji T, Esum M, Che JN, Nkwescheu A, et al. Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis in Cameroon. Parasit Vectors 2009; 2 : 39.  Back to cited text no. 50
Waters HR, Rehwinkel JA, Burnham G. Economic evaluation of Mectizan distribution. Trop Med Int Health 2004; 9 : A16-25.  Back to cited text no. 51
Suputtamongkol Y, Niwattayakul K, Suttinont C, Losuwanaluk K, Limpaiboon R, Chierakul W, et al. An open, randomized, controlled trial of penicillin, doxycycline, and cefotaxime for patients with severe leptospirosis. Clin Infect Dis 2004; 39 : 1417-24.  Back to cited text no. 52
Brouillard JE, Terriff CM, Tofan A, Garrison MW. Antibiotic selection and resistance issues with fluoroquinolones and doxycycline against bioterrorism agents. Pharmacotherapy 2006; 26 : 3-14.  Back to cited text no. 53
U.S. National Library of Medicine, National Center for Biotechnology Information. PubChem Database. Doxycycline, CID=54671203. Available from:, accessed on June 9, 2019.  Back to cited text no. 54
Townson S, Hutton D, Siemienska J, Hollick L, Scanlon T, Tagboto SK, et al. Antibiotics and Wolbachia in filarial nematodes: Antifilarial activity of rifampicin, oxytetracycline and chloramphenicol against Onchocerca gutturosa, Onchocerca lienalis and Brugia pahangi. Ann Trop Med Parasitol 2000; 94 : 801-16.  Back to cited text no. 55
Volkmann L, Fischer K, Taylor M, Hoerauf A. Antibiotic therapy in murine filariasis (Litomosoides sigmodontis): Comparative effects of doxycycline and rifampicin on Wolbachia and filarial viability. Trop Med Int Health 2003; 8 : 392-401.  Back to cited text no. 56
Rao R, Well GJ. In vitro effects of antibiotics on Brugia malayi worm survival and reproduction. J Parasitol 2002; 88 : 605-11.  Back to cited text no. 57
Hoerauf A, Marfo-Debrekyei Y, Büttner M, Debrah AY, Konadu P, Mand S, et al. Effects of 6-week azithromycin treatment on the Wolbachia endobacteria of Onchocerca volvulus. Parasitol Res 2008; 103 : 279-86.  Back to cited text no. 58
Richards FO Jr., Amann J, Arana B, Punkosdy G, Klein R, Blanco C, et al. No depletion of Wolbachia from Onchocerca volvulus after a short course of rifampin and/or azithromycin. Am J Trop Med Hyg 2007; 77 : 878-82.  Back to cited text no. 59
Arnold CJ, Ericson J, Kohman J, Corey KL, Oh M, Onabanjo J, et al. Rifampin use and safety in hospitalized infants. Am J Perinatol 2015; 32 : 565-70.  Back to cited text no. 60
Specht S, Mand S, Marfo-Debrekyei Y, Debrah AY, Konadu P, Adjei O, et al. Efficacy of 2- and 4-week rifampicin treatment on the Wolbachia of Onchocerca volvulus. Parasitol Res 2008; 103 : 1303-9.  Back to cited text no. 61
Turner JD, Sharma R, Al Jayoussi G, Tyrer HE, Gamble J, Hayward L, et al. Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis. Proc Natl Acad Sci U S A 2017; 114 : E9712-21.  Back to cited text no. 62
Goldstein BP. Resistance to rifampicin: A review. J Antibiot (Tokyo) 2014; 67 : 625-30.  Back to cited text no. 63
Aljayyoussi G, Tyrer HE, Ford L, Sjoberg H, Pionnier N, Waterhouse D, et al. Short-course, high-dose rifampicin achieves Wolbachia depletion predictive of curative outcomes in preclinical models of lymphatic filariasis and onchocerciasis. Sci Rep 2017; 7 : 210.  Back to cited text no. 64
Garrido-Mesa N, Zarzuelo A, Gálvez J. Minocycline: Far beyond an antibiotic. Br J Pharmacol 2013; 169 : 337-52.  Back to cited text no. 65
Townson S, Tagboto S, McGarry HF, Egerton GL, Taylor MJ. Onchocerca parasites and Wolbachia endosymbionts: Evaluation of a spectrum of antibiotic types for activity against Onchocerca gutturosa in vitro. Filaria J 2006; 5 : 4.  Back to cited text no. 66
Sharma R, Al Jayoussi G, Tyrer HE, Gamble J, Hayward L, Guimaraes AF, et al. Minocycline as a re-purposed anti-Wolbachia macrofilaricide: Superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis. Sci Rep 2016; 6 : 23458.  Back to cited text no. 67
Klarmann-Schulz U, Specht S, Debrah AY, Batsa L, Ayisi-Boateng NK, Osei-Mensah J, et al. Comparison of doxycycline, minocycline, doxycycline plus albendazole and albendazole alone in their efficacy against onchocerciasis in a randomized, open-label, pilot trial. PLoS Negl Trop Dis 2017; 11 : e0005156.  Back to cited text no. 68
Irschik H, Jansen R, Höfle G, Gerth K, Reichenbach H. The corallopyronins, new inhibitors of bacterial RNA synthesis from myxobacteria. J Antibiot (Tokyo) 1985; 38 : 145-52.  Back to cited text no. 69
Schiefer A, Schmitz A, Schäberle TF, Specht S, Lämmer C, Johnston KL, et al. Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo. J Infect Dis 2012; 206 : 249-57.  Back to cited text no. 70
Schäberle TF, Schiefer A, Schmitz A, König GM, Hoerauf A, Pfarr K, et al. Corallopyronin A – A promising antibiotic for treatment of filariasis. Int J Med Microbiol 2014; 304 : 72-8.  Back to cited text no. 71
The efficacy of rifapentine plus moxifloxacin against onchocerciasis: A randomized, open label pilot trial. Trial No. ISRCTN43697583. Available from:, accessed on May 23, 2016.  Back to cited text no. 72
Johnston KL, Ford L, Umareddy I, Townson S, Specht S, Pfarr K, et al. Repurposing of approved drugs from the human pharmacopoeia to target Wolbachia endosymbionts of onchocerciasis and lymphatic filariasis. Int J Parasitol Drugs Drug Resist 2014; 4 : 278-86.  Back to cited text no. 73
Li Z, Garner AL, Gloeckner C, Janda KD, Carlow CK. Targeting the Wolbachia cell division protein FtsZ as a new approach for antifilarial therapy. PLoS Negl Trop Dis 2011; 5 : e1411.  Back to cited text no. 74
Voronin D, Cook DAN, Steven A, Taylor MJ. Autophagy regulates Wolbachia populations across diverse symbiotic associations. Proc Natl Acad Sci U S A 2012; 109 : E1638-46.  Back to cited text no. 75
Johnston KL, Wu B, Guimarães A, Ford L, Slatko BE, Taylor MJ, et al. Lipoprotein biosynthesis as a target for anti-Wolbachia treatment of filarial nematodes. Parasit Vectors 2010; 3 : 99.  Back to cited text no. 76
Wu B, Novelli J, Foster J, Vaisvila R, Conway L, Ingram J, et al. The heme biosynthetic pathway of the obligate Wolbachia endosymbiont of Brugia malayi as a potential anti-filarial drug target. PLoS Negl Trop Dis 2009; 3 : e475.  Back to cited text no. 77


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