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

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 scr...

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Autores principales: Halliday, Alice, Guimaraes, Ana F, Tyrer, Hayley E, Metuge, Haelly Mejane, Patrick, Chounna Ndongmo Winston, Arnaud, Kengne-Ouafo Jonas, Kwenti, Tayong Dizzle Bita, Forsbrook, George, Steven, Andrew, Cook, Darren, Enyong, Peter, Wanji, Samuel, Taylor, Mark J, Turner, Joseph D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212127/
https://www.ncbi.nlm.nih.gov/pubmed/25338621
http://dx.doi.org/10.1186/s13071-014-0472-z
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author Halliday, Alice
Guimaraes, Ana F
Tyrer, Hayley E
Metuge, Haelly Mejane
Patrick, Chounna Ndongmo Winston
Arnaud, Kengne-Ouafo Jonas
Kwenti, Tayong Dizzle Bita
Forsbrook, George
Steven, Andrew
Cook, Darren
Enyong, Peter
Wanji, Samuel
Taylor, Mark J
Turner, Joseph D
author_facet Halliday, Alice
Guimaraes, Ana F
Tyrer, Hayley E
Metuge, Haelly Mejane
Patrick, Chounna Ndongmo Winston
Arnaud, Kengne-Ouafo Jonas
Kwenti, Tayong Dizzle Bita
Forsbrook, George
Steven, Andrew
Cook, Darren
Enyong, Peter
Wanji, Samuel
Taylor, Mark J
Turner, Joseph D
author_sort Halliday, Alice
collection PubMed
description 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.
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spelling pubmed-42121272014-10-30 A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis Halliday, Alice Guimaraes, Ana F Tyrer, Hayley E Metuge, Haelly Mejane Patrick, Chounna Ndongmo Winston Arnaud, Kengne-Ouafo Jonas Kwenti, Tayong Dizzle Bita Forsbrook, George Steven, Andrew Cook, Darren Enyong, Peter Wanji, Samuel Taylor, Mark J Turner, Joseph D Parasit Vectors Research 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. BioMed Central 2014-10-24 /pmc/articles/PMC4212127/ /pubmed/25338621 http://dx.doi.org/10.1186/s13071-014-0472-z Text en © Halliday et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Halliday, Alice
Guimaraes, Ana F
Tyrer, Hayley E
Metuge, Haelly Mejane
Patrick, Chounna Ndongmo Winston
Arnaud, Kengne-Ouafo Jonas
Kwenti, Tayong Dizzle Bita
Forsbrook, George
Steven, Andrew
Cook, Darren
Enyong, Peter
Wanji, Samuel
Taylor, Mark J
Turner, Joseph D
A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
title A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
title_full A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
title_fullStr A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
title_full_unstemmed A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
title_short A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
title_sort murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212127/
https://www.ncbi.nlm.nih.gov/pubmed/25338621
http://dx.doi.org/10.1186/s13071-014-0472-z
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