A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis.
A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis.
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DOI：
10.1186/s13071-014-0472-z
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发表时间：
2014-10-24
影响因子：
3.2
通讯作者：
Turner JD
中科院分区：
文献类型：
--
作者：
Halliday A;Guimaraes AF;Tyrer HE;Metuge HM;Patrick CN;Arnaud KO;Kwenti TD;Forsbrook G;Steven A;Cook D;Enyong P;Wanji S;Taylor MJ;Turner JD
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. 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. 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. 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.
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影响因子：
3.7
作者：
Attout T;Hoerauf A;Dénécé G;Debrah AY;Marfo-Debrekyei Y;Boussinesq M;Wanji S;Martinez V;Mand S;Adjei O;Bain O;Specht S;Martin C
通讯作者：
Martin C
影响因子：
3.1
作者：
Folkard, SG;Taylor, MJ;Bianco, AE
通讯作者：
Bianco, AE
DOI：
10.1073/pnas.0906176106
发表时间：
2009-09-29
影响因子：
11.1
作者：
Churcher, Thomas S.;Pion, Sebastien D. S.;Basanaz, Maria-Gloria
通讯作者：
Basanaz, Maria-Gloria
影响因子：
1.6
作者：
DEVANEY, E;HOWELLS, RE;SMITH, G
通讯作者：
SMITH, G
影响因子：
3.2
作者：
Dec Bronsvoort BM;Makepeace BL;Renz A;Tanya VN;Fleckenstein L;Ekale D;Trees AJ
通讯作者：
Trees AJ