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‐Martínez, 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.; Voorhis, Wes Van; Hemphill, Andrew

doi:10.1093/jac/dkx134

Cited by 48 publications

(57 citation statements)

References 48 publications

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“…There was slight dissemination of the parasite in the lambs with no antibodies detected by IFAT, although this technique may suffer from low sensitivity (7). These results are in line with those from a pregnant mouse model of toxoplasmosis, in which 100% protection against pup mortality and 93% protection against vertical transmission in the surviving offspring was accomplished with BKI-1294 (28). The increased protection of BKI-1294 in pregnant mice compared to pregnant sheep could be explained by the lower offspring mortality and vertical transmission of T. gondii in mice compared to that in sheep (36).…”

Section: Discussionsupporting

confidence: 79%

“…Previous drugs tested against T. gondii in pregnant sheep were dosed starting 10 days prior to infection until parturition (12,13,15). However, in this study the beginning of BKI-1294 treatment was planned 48 h after infection, in the same way as previous studies of BKI therapy of toxoplasmosis in mice (27,28,35). At this time point, the infection has already been established and the parasites have been widely distributed in the animals.…”

Section: Discussionmentioning

confidence: 99%

“…BKIs have broad-spectrum activity that affects many apicomplexan parasites (24). BKI-1294 is effective against T. gondii in vitro (25) and in vivo against acute (26,27) and chronic (26) toxoplasmosis in mice, as well as against vertical transmission in a pregnant mouse model of toxoplasmosis (28).…”

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confidence: 99%

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Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Sánchez-Sánchez

Ferre

et al. 2019

Antimicrob Agents Chemother

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Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 M and trough concentrations of 0.4 M at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Sánchez-Sánchez

Ferre

et al. 2019

Antimicrob Agents Chemother

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“…Females were oestrus-synchronized by the Whitten effect [22] and were mated for three nights (1 male per 2 females), after which males were removed from the cages. All BKIs (see Table 1) were suspended in corn oil and administered by oral gavage (50mg/kg/day in 100μl) from day 9 to day 13 post-mating as described earlier for BKI-1294 treatment [20, 22, 23]. The only exception is BKI-1796, which was administered at 25mg/kg body weight on days 1, 3 and 5.…”

Section: Methodsmentioning

confidence: 99%

“…However, in pregnant BALB/c mice infected with N. caninum , BKI-1294 had a profound impact on vertical transmission and offspring mortality [25]. Similarly, BKI-1294 impacted on T. gondii oocyst infection in pregnant CD1 mice, achieving 100% offspring survival and significant inhibition of vertical transmission [20]. Two other BKIs, −1517 and −1553, also inhibited N. caninum proliferation in vitro , and were highly efficacious and safe in non-pregnant mice, but were shown to interfere in pregnancy outcome in N. caninum infected mice [23].…”

Section: Introductionmentioning

confidence: 99%

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

Anghel

Winzer

Imhof

et al. 2020

Preprint

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Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice, were assessed in pregnant mice. Drugs were emulsified in corn oil and applied by gavage for 5 days. Five BKIs did not affect pregnancy, 5 BKIs exhibited 15-35% of neonatal mortality, and 5 compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilized eggs to 0.2-50μM of BKIs and microscopical monitoring of embryo development in a blinded manner during 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows to calculate an impact score (Si) that indicates at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for 9 compounds no clear correlation between Si and pregnancy outcome was visible. However, those 3 BKIs affecting zebrafish embryos only at high concentrations (40μM or higher) did not impair mouse pregnancy at all, and those 3 compounds that inhibited zebrafish embryo development already at 0.2μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has a limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude, that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects.

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Recent Trends in Toxoplasmosis Diagnosis and Management

Chorawala,

Kothari,

Shah

et al. 2024

Rising Contagious Diseases

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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

Abstract: BKI-1294 and buparvaquone exert excellent activities against transplacental transmission in pregnant mice.

Cited by 48 publications

References 48 publications

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

Recent Trends in Toxoplasmosis Diagnosis and Management

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