Development of a murine vertical transmission model for Toxoplasma gondii oocyst infection and studies on the efficacy of bumped kinase inhibitor (BKI)-1294 and the naphthoquinone buparvaquone against congenital toxoplasmosis.

Müller, Joachim; Aguado Martinez, Adriana; Ortega-Mora, Luis-Miguel; Moreno-Gonzalo, Javier; Ferre, Ignacio; Hulverson, Matthew A; Choi, Ryan; McCloskey, Molly C; Barrett, Lynn K; Maly, Dustin J; Ojo, Kayode K; Van Voorhis, Wes; Hemphill, Andrew (2017). Development of a murine vertical transmission model for Toxoplasma gondii oocyst infection and studies on the efficacy of bumped kinase inhibitor (BKI)-1294 and the naphthoquinone buparvaquone against congenital toxoplasmosis. Journal of antimicrobial chemotherapy, 72(8), pp. 2334-2341. Oxford University Press 10.1093/jac/dkx134

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Objectives Establishment of a mouse model for congenital toxoplasmosis based on oral infection with oocysts from Toxoplasma gondii ME49 and its application for investigating chemotherapeutic options against congenital toxoplasmosis. Methods CD1 mice were mated, orally infected with 5, 25, 100, 500 or 2000 oocysts and monitored for clinical signs and survival of dams and pups until 4 weeks post partum . The parasite burden in infected mice was quantified by real-time PCR in lungs, brains and, in the case of surviving pups, also in eyes. Seroconversion was assessed by ELISA. T. gondii cysts in brain were identified by immunofluorescence. In a second experiment, pregnant CD1 mice challenged with 20 oocysts/mouse were treated with buparvaquone or the calcium-dependent protein kinase 1 inhibitor bumped kinase inhibitor (BKI)-1294 and the outcome of infection was analysed. Results T. gondii DNA was detected in the brain of all infected animals, irrespective of the infection dose. Seroconversion occurred at 3 weeks post-infection. Most pups born to infected dams died within 1 week post partum , but a small fraction survived until the end of the experiment. T. gondii DNA was detected in the brain of all survivors and half of them exhibited ocular infection. Chemotherapy with both compounds led to dramatically increased numbers of surviving pups and reduced cerebral infection. Most efficient were treatments with BKI-1294, with 100% survivors and only 7% brain-positive pups. Conclusions BKI-1294 and buparvaquone exert excellent activities against transplacental transmission in pregnant mice.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Müller, Joachim; Aguado Martinez, Adriana and Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture
500 Science > 540 Chemistry
500 Science > 570 Life sciences; biology

ISSN:

0305-7453

Publisher:

Oxford University Press

Language:

English

Submitter:

Andrew Hemphill

Date Deposited:

17 May 2018 17:26

Last Modified:

16 Aug 2018 15:20

Publisher DOI:

10.1093/jac/dkx134

PubMed ID:

28486633

BORIS DOI:

10.7892/boris.113113

URI:

https://boris.unibe.ch/id/eprint/113113

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