In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae.
Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia dep...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-08-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0007636 |
| _version_ | 1818478792446836736 |
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| author | Marc P Hübner Marianne Koschel Dominique Struever Venelin Nikolov Stefan J Frohberger Alexandra Ehrens Martina Fendler Iliana Johannes Thomas W von Geldern Kennan Marsh Joseph D Turner Mark J Taylor Stephen A Ward Kenneth Pfarr Dale J Kempf Achim Hoerauf |
| author_facet | Marc P Hübner Marianne Koschel Dominique Struever Venelin Nikolov Stefan J Frohberger Alexandra Ehrens Martina Fendler Iliana Johannes Thomas W von Geldern Kennan Marsh Joseph D Turner Mark J Taylor Stephen A Ward Kenneth Pfarr Dale J Kempf Achim Hoerauf |
| author_sort | Marc P Hübner |
| collection | DOAJ |
| description | Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3-4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed. |
| first_indexed | 2024-12-10T09:52:32Z |
| format | Article |
| id | doaj.art-938a56b59b9342c292856f5bada424f0 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-10T09:52:32Z |
| publishDate | 2019-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-938a56b59b9342c292856f5bada424f02022-12-22T01:53:38ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352019-08-01138e000763610.1371/journal.pntd.0007636In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae.Marc P HübnerMarianne KoschelDominique StrueverVenelin NikolovStefan J FrohbergerAlexandra EhrensMartina FendlerIliana JohannesThomas W von GeldernKennan MarshJoseph D TurnerMark J TaylorStephen A WardKenneth PfarrDale J KempfAchim HoeraufDepletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3-4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed.https://doi.org/10.1371/journal.pntd.0007636 |
| spellingShingle | Marc P Hübner Marianne Koschel Dominique Struever Venelin Nikolov Stefan J Frohberger Alexandra Ehrens Martina Fendler Iliana Johannes Thomas W von Geldern Kennan Marsh Joseph D Turner Mark J Taylor Stephen A Ward Kenneth Pfarr Dale J Kempf Achim Hoerauf In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. PLoS Neglected Tropical Diseases |
| title | In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. |
| title_full | In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. |
| title_fullStr | In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. |
| title_full_unstemmed | In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. |
| title_short | In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. |
| title_sort | in vivo kinetics of wolbachia depletion by abbv 4083 in l sigmodontis adult worms and microfilariae |
| url | https://doi.org/10.1371/journal.pntd.0007636 |
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