Abstract
BackgroundNew drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.MethodsThe filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7–15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca.ResultsWT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.ConclusionsWe have developed a ‘pan-filarial’ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.
Highlights
New drugs effective against adult filariae would accelerate the elimination of lymphatic filariasis and onchocerciasis
Evaluating the performance of reference filaricidal compounds against B. malayi in Severe-Combined ImmunoDeficiency (SCID) mice We adapted mouse models of Brugian filariasis [26,27,28] to scrutinise whether the standard anti-filarial drugs (SAFD) albendazole (ABZ), diethylcarbamazine (DEC) and ivermectin (IVM) or drugs with demonstrated macrofilaricidal properties, flubendazole (FBZ) and the tetracycline antiwolbachia antibiotic, minocycline (MIN), displayed predictable efficacy in a Severe-Combined Immuno-Deficiency (SCID) mouse model system
Infected mice were orally administered with SAFD or vehicle control (VC) at indicated doses for seven days, before Brugia malayi (Bm) larvae were recovered by peritoneal lavage (+24 h following the final drug exposure) and motile parasites enumerated
Summary
New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. The emergence of sub-optimal responders to IVM following repetitive treatments [5] and the risk of severe adverse reactions in patients co-infected with the bloodborne filaria, Loa loa [6], exert additional challenges on maintaining control of onchocerciasis. Drugs effective at killing adult Onchocerca (macrofilaricides), would be desirable to address this pressing global health problem and accelerate the ultimate elimination of onchocerciasis. New macrofilaricides may well have useful indications against the causative agents of lymphatic filariasis; LF (Wuchereria bancrofti, Brugia malayi, B. timori), especially to reduce the long tail of ‘endgame mop-up’ in countries that have completed extensive elimination programmes or in ‘hard to reach’ areas [1]
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