Saturday, August 08, 2015

Effects of the bumped kinase inhibitor 1294 in the related cyst-forming apicomplexans Toxoplasma gondii and Neospora caninum

 2015 Jul 27. pii: AAC.01236-15. [Epub ahead of print]


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.
[PubMed - as supplied by publisher]


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