Winzer P1,
Müller J1,
Aguado-Martínez A1,
Rahman M1,
Balmer V1,
Manser V1,
Ortega-Mora LM2,
Ojo KK3,
Fan E4,
Maly DJ5,
Van Voorhis WC3,
Hemphill A6.
Abstract
We here report on the in vitro effects of the bumped kinase inhibitor 1294 (BKI-1294) in cultures of the virulent Neospora caninum isolates Nc-Liverpool (Nc-Liv) and Nc-Spain7 and in two strains of Toxoplasma gondii (RH and ME49), all grown in human foreskin fibroblasts. In these parasites BKI-1294 acted with IC50s ranging from 20 nM (T. gondii RH) to 360 nM (N. caninum Nc-Liv), and exposure of intracellular stages to 1294 lead to non-disjunction of newly formed tachyzoites, resulting in the formation of multinucleated complexes similar to complexes earlier observed in BKI-1294-treated N. caninum beta-galactosidase-expressing parasites. However, such complexes were not seen in a transgenic T. gondii strain that expressed CDPK1 harboring a mutation (G-M) in the gatekeeper residue. In T. gondii ME49 and N. caninum Nc-Liv, exposure of cultures to BKI-1294 resulted in 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, the BKI-1294 efficiently inhibited vertical transmission in Balb/c mice experimentally infected with 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 subject of future studies.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
- PMID:
- 26248379
- [PubMed - as supplied by publisher]
2 comments:
The greater part of critics are parasites, who, if nothing had been written, would find nothing to write. See the link below for more info.
#parasites
www.ufgop.org
Rhein is an anthraquinone compound enriched in the fresh rhizome of Rheum coreanum Nakai, showing anti-inflammation and antitumor activities. Rheic Acid
Post a Comment