title: A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis.
abstract: BACKGROUND
  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. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  WT 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. alice.halliday@gmail.com.
authors.forename: Alice
authors.initials: A
authors.lastname: Halliday
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. ana.filipaguedes@gmail.com.
authors.forename: Ana F
authors.initials: AF
authors.lastname: Guimaraes
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. Hayley.Tyrer@lstmed.ac.uk.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Tyrer
authors.affiliation: Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. meganeheally@yahoo.co.uk.
authors.forename: Haelly Mejane
authors.initials: HM
authors.lastname: Metuge
authors.affiliation: Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. ndongmopatrick@yahoo.com.|Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. ndongmopatrick@yahoo.com.
authors.forename: Chounna Ndongmo Winston
authors.initials: CN
authors.lastname: Patrick
authors.affiliation: Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. jakengne@gmail.com.|Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. jakengne@gmail.com.
authors.forename: Kengne-Ouafo Jonas
authors.initials: KO
authors.lastname: Arnaud
authors.affiliation: Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. b.tayong@yahoo.com.|Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. b.tayong@yahoo.com.
authors.forename: Tayong Dizzle Bita
authors.initials: TD
authors.lastname: Kwenti
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. georgeforsbrook@gmail.com.
authors.forename: George
authors.initials: G
authors.lastname: Forsbrook
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. Andrew.steven@lstmed.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Steven
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. Darren.cook@lstmed.ac.uk.
authors.forename: Darren
authors.initials: D
authors.lastname: Cook
authors.affiliation: Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. penyongap@yahoo.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Enyong
authors.affiliation: Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. swanji@yahoo.fr.|Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. swanji@yahoo.fr.
authors.forename: Samuel
authors.initials: S
authors.lastname: Wanji
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. mark.taylor@lstmed.ac.uk.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Taylor
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. joseph.turner@lstmed.ac.uk.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Turner
mesh_terms: D000818:Animals; D017178:Brugia malayi; D004605:Elephantiasis, Filarial / Q000188:drug therapy*; D005260:Female; D005369:Filaricides / Q000494:pharmacology*; D005849:Gerbillinae; D008297:Male; D008596:Menotropins; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009854:Onchocerca; D009855:Onchocerciasis / Q000188:drug therapy*
chemical_list: D005369:Filaricides; C527545:hMG-IBSA; D008596:Menotropins