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Parasit Vectors. 2014 Oct 24;7:472. doi: 10.1186/s13071-014-0472-z.

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis.

Author information

1
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. alice.halliday@gmail.com.
2
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. ana.filipaguedes@gmail.com.
3
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. Hayley.Tyrer@lstmed.ac.uk.
4
Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. meganeheally@yahoo.co.uk.
5
Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. ndongmopatrick@yahoo.com.
6
Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. ndongmopatrick@yahoo.com.
7
Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. jakengne@gmail.com.
8
Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. jakengne@gmail.com.
9
Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. b.tayong@yahoo.com.
10
Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. b.tayong@yahoo.com.
11
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. georgeforsbrook@gmail.com.
12
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. Andrew.steven@lstmed.ac.uk.
13
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. Darren.cook@lstmed.ac.uk.
14
Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. penyongap@yahoo.com.
15
Research Foundation for Tropical Diseases and the Environment, Buea, Cameroon. swanji@yahoo.fr.
16
Department of Microbiology and Parasitology, Parasite and Vector Research Unit, University of Buea, Buea, Cameroon. swanji@yahoo.fr.
17
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. mark.taylor@lstmed.ac.uk.
18
Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK. joseph.turner@lstmed.ac.uk.

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.

PMID:
25338621
PMCID:
PMC4212127
DOI:
10.1186/s13071-014-0472-z
[Indexed for MEDLINE]
Free PMC Article

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