scholarly journals 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

2017 ◽  
Vol 72 (8) ◽  
pp. 2334-2341 ◽  
Author(s):  
Joachim Müller ◽  
Adriana Aguado-Martínez ◽  
Luis-Miguel Ortega-Mora ◽  
Javier Moreno-Gonzalo ◽  
Ignacio Ferre ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Kinase Inhibitor ◽  
Congenital Toxoplasmosis ◽  
Transmission Model ◽  
Bumped Kinase Inhibitor

scholarly journals In VitroandIn VivoEffects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum

2015 ◽  
Vol 59 (10) ◽  
pp. 6361-6374 ◽  
Author(s):  
Pablo Winzer ◽  
Joachim Müller ◽  
Adriana Aguado-Martínez ◽  
Mahbubur Rahman ◽  
Vreni Balmer ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Kinase Inhibitor ◽  
Neospora Caninum ◽  
Antigen Expression ◽  
Pregnant Mouse ◽  
Content Type ◽  
Elevated Expression ◽  
Bumped Kinase Inhibitor

ABSTRACTWe report on thein vitroeffects of the bumped kinase inhibitor 1294 (BKI-1294) in cultures of virulentNeospora caninumisolates Nc-Liverpool (Nc-Liv) and Nc-Spain7 and in two strains ofToxoplasma gondii(RH and ME49), all grown in human foreskin fibroblasts. In these parasites, BKI-1294 acted with 50% inhibitory concentrations (IC50s) ranging from 20 nM (T. gondiiRH) to 360 nM (N. caninumNc-Liv), and exposure of intracellular stages to 1294 led to the nondisjunction of newly formed tachyzoites, resulting in the formation of multinucleated complexes similar to complexes previously observed in BKI-1294-treatedN. caninumbeta-galactosidase-expressing parasites. However, such complexes were not seen in a transgenicT. gondiistrain that expressed CDPK1 harboring a mutation (G to M) in the gatekeeper residue. InT. gondiiME49 andN. caninumNc-Liv, exposure of cultures to BKI-1294 resulted in the elevated expression of mRNA coding for the bradyzoite marker BAG1. Unlike in bradyzoites, SAG1 expression was not repressed. Immunofluorescence also showed that these multinucleated complexes expressed SAG1 and BAG1 and the monoclonal antibody CC2, which binds to a yet unidentified bradyzoite antigen, also exhibited increased labeling. In a pregnant mouse model, BKI-1294 efficiently inhibited vertical transmission in BALB/c mice experimentally infected with one of the two virulent isolates Nc-Liv or Nc-Spain7, demonstrating proof of concept that this compound protected offspring from vertical transmission and disease. The observed deregulated antigen expression effect may enhance the immune response during BKI-1294 therapy and will be the subject of future studies.

scholarly journals 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

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Roberto Sánchez-Sánchez ◽  
Ignacio Ferre ◽  
Michela Re ◽  
Juan José Ramos ◽  
Javier Regidor-Cerrillo ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Fetal Mortality ◽  
Maximum Plasma ◽  
Content Type ◽  
Pregnant Sheep

ABSTRACT 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 μM and trough concentrations of 0.4 μM 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.

scholarly journals Bumped Kinase Inhibitor 1294 Treats Established Toxoplasma gondii Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3547-3549 ◽  
Author(s):  
J. Stone Doggett ◽  
Kayode K. Ojo ◽  
Erkang Fan ◽  
Dustin J. Maly ◽  
Wesley C. Van Voorhis
Keyword(s):  
Toxoplasma Gondii ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Content Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Orally Bioavailable ◽  
Toxoplasma Gondii Infection ◽  
Bumped Kinase Inhibitor

ABSTRACTToxoplasma gondiiis a unicellular parasite that causes severe brain and eye disease. Current drugs forT. gondiiare limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogensT. gondii, cryptosporidia, and plasmodia. A lead anti-ToxoplasmaBKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosisin vivo.

scholarly journals Toxoplasma gondii immunoglobulin G in paired infant-and-mother sera

2009 ◽  
Vol 49 (2) ◽  
pp. 65
Author(s):  
Ayling Sanjaya ◽  
Nurhayati Masloman ◽  
Rocky Wilar ◽  
Josef Tuda
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Immunoglobulin G ◽  
Congenital Toxoplasmosis ◽  
Cross Sectional Study ◽  
Latex Agglutination ◽  
Sectional Study ◽  
Cross Sectional ◽  
Blood Specimen ◽  
Agglutination Method

Background  Toxoplasmosis  is  a worldwide zoonotic diseasecaused  by  Toxoplasma  gondii.  Congenital toxoplasmosis (CT)is  the  result  of  vertical transmission  during  pregnancy  thatmay cause pathologic effects  on  the newborn such  as  classicaltriad  of  congenital toxoplasmosis.  Newborn  humans  are  notimmunologically  competent  and the infant must be protected  by passive lgG antibodies  that  are selectively transported across the placenta during development.  We  studied the transfer  of  passive lgG from the  mother  to developing infant using blood specimen taken from the infant within one  month  of  birth.Objective  To  determine the seropositivity  of  lgG to  T.  gondii  in paired sera  of  infants and mothers.Methods  A cross sectional study was carried  out  on  50 pairedsera  of  infants  of  less  than  one  month  of  age and their mothers. The  study was carried  out  between November 2007 and January 2008  at  Prof.  R.  D.  Kandou Hospital in Manado.  T.  gondii  lgG was detected using the Latex Agglutination method.  The  seropositivity ofT.  gondii  lgG was analyzed descriptively.Results  A total  of  28 mothers from 50 infant-mother pairs wereseropositive for  T.  gondii  IgG.  Of  the 28 seropositive mothers, 22  of their paired infants were seropositive.  The  remaining six seropositive mothers  had  infants  that  were  not  seropositive for T.  gondii.Conclusions  The  identification  of  seropositive lgG for  T.  gondii in infants less  than  one  months  age indicates  that  the lgGs in infants are mostly derived from their mothers.  CT  must be considered  and  further  examinations  are needed.

scholarly journals A Novel Calcium-Dependent Protein Kinase 1 Inhibitor Potently Prevents Toxoplasma gondii Transmission to Foetuses in Mouse

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4203
Author(s):  
Héloïse Débare ◽  
Nathalie Moiré ◽  
Firmin Baron ◽  
Louis Lantier ◽  
Bruno Héraut ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Intraperitoneal Administration ◽  
Congenital Toxoplasmosis ◽  
Parasite Burden ◽  
Oral Route ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Calcium Dependent Protein Kinase

Treatments currently used to prevent congenital toxoplasmosis are non-specific of Toxoplasma gondii and have grievous side effects. To develop a more specific and less toxic drug, we have designed SP230, an imidazo[1,2-b]pyridazine salt targeting the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) and active against acute toxoplasmosis in mice. Efficiency of SP230 to inhibit foetal transmission of the parasite was evaluated in a mouse model of congenital toxoplasmosis. Swiss mice were infected at mid-pregnancy with tachyzoites or cysts of the ME49 strain of T. gondii by intraperitoneal and oral route, respectively, and treated with SP230 at 50 mg/kg for 5 days by the same routes. Parasite burden in organs of dams and in foetuses was measured by quantitative PCR. Intraperitoneal administration of SP230 drastically reduced the number of parasites (more than 97% of reduction) in the brain and lungs of dams, and led to a reduction of 66% of parasite burden in foetuses. Oral administration of SP230 was particularly efficient with 97% of reduction of parasite burdens in foetuses. SP230 did not impact number and weight of offspring in our conditions. This inhibitor of TgCDPK1 is a promising candidate for the development of alternative therapeutics to treat infected pregnant women.

scholarly journals Calomys callosus chronically infected by Toxoplasma gondii clonal type II strain and reinfected by Brazilian strains is not able to prevent vertical transmission

2015 ◽  
Vol 6 ◽  
Author(s):  
Priscila S. Franco ◽  
Neide M. da Silva ◽  
Bellisa de Freitas Barbosa ◽  
Angelica de Oliveira Gomes ◽  
Francesca Ietta ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Type Ii ◽  
Clonal Type ◽  
Calomys Callosus

scholarly journals Seroprevalence of toxoplasmosis in Vojvodina

2010 ◽  
Vol 138 (5-6) ◽  
pp. 333-336 ◽  
Author(s):  
Snezana Brkic ◽  
Gorana Gajski ◽  
Mirjana Bogavac ◽  
Daniela Maric ◽  
Vesna Turkulov ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
General Population ◽  
Pregnant Women ◽  
Acute Infection ◽  
Clinical Manifestations ◽  
Congenital Toxoplasmosis ◽  
Reproductive Age ◽  
Female Population ◽  
Effective Measure ◽  
Female Patients

Introduction Toxoplasmosis is an acute infectious anthropozoonotic disease with mild asymptomatic clinical manifestations in immunocompetent persons and more severe in immunocompromised patients. Acute infection in pregnancy can result in severe congenital toxoplasmosis with severe sequels. Objective Aims of study were to detect Toxoplasma gondii seroprevalence in general population of Vojvodina, Serbia, differences between genders and determination of seroprevalence in women of reproductive age and pregnant women. Methods Our retrospective study was conducted from 2006 to 2008 including 625 immunocompetent patients, hospitalized or observed as outpatients at the Clinical Centre of Vojvodina, Novi Sad. We performed commercial ELISA kits SERION - ELISA classic test by VIRION for the presence of specific IgG and IgM antibodies. According to seroepidemiological aim of the study, our results were presented only in qualitative values. Results We observed 173 male and 452 female patients. Seroprevalence in general population of Vojvodina was 38.1%. In male population seroprevalence was 45.7%, and in female population it was 35.2%, the difference which was statistically significant (p<0.05). Seroprevalence increased with age and seroconversion was detected to occur in persons aged about 20 years. In all female patients, 353 (78.1%) were in reproductive age with seroprevalence of 30%. In 161 pregnant women seroprevalence was 31.7%. Conclusion In this study we screened actual seroepidemiological situation to Toxoplasma gondii in Vojvodina, thus giving a contribution to the continuous epidemiological screening done in this region and in the country. According to our results, almost 70% of women in reproductive age were sensitive to primary acute infection during further pregnancies, which is highly important for the prevention of congenital toxoplasmosis. Although not routinely conducted in many countries, routine serological testing to Toxoplasma gondii in pregnant women and their education about preventive measures against this infection could be an effective measure in the future.

scholarly journals Zika viruses of both African and Asian lineages cause fetal harm in a vertical transmission model

2018 ◽  
Author(s):  
Anna S. Jaeger ◽  
Reyes A. Murreita ◽  
Lea R. Goren ◽  
Chelsea M. Crooks ◽  
Ryan V. Moriarty ◽  
...  
Keyword(s):  
Mouse Model ◽  
Vertical Transmission ◽  
Birth Defects ◽  
Asian American ◽  
Zika Virus ◽  
French Polynesia ◽  
Transmission Model ◽  
Foreseeable Future ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

AbstractCongenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak 1–3. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS) 4,5. Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas 5. Here we show that African ZIKV can infect and harm fetuses and that the S139N mutation that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.

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