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Neospora caninum: Differential Proteome of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294

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Winzer, Pablo and Müller, Joachim and Imhof, Dennis and Ritler, Dominic and Uldry, Anne-Christine and Braga-Lagache, Sophie and Heller, Manfred and Ojo, Kayode K. and Van Voorhis, Wesley C. and Ortega Mora, Luis Miguel and Hemphill, Andrew (2020) Neospora caninum: Differential Proteome of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294. Microorganisms, 8 (6). p. 801. ISSN 2076-2607

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Official URL: https://doi.org/10.3390/microorganisms8060801




Abstract

Background: the apicomplexan parasite Neospora caninum causes important reproductive problems in farm animals, most notably in cattle. After infection via oocysts or tissue cysts, rapidly dividing tachyzoites infect various tissues and organs, and in immunocompetent hosts, they differentiate into slowly dividing bradyzoites, which form tissue cysts and constitute a resting stage persisting within infected tissues. Bumped kinase inhibitors (BKIs) of calcium dependent protein kinase 1 are promising drug candidates for the treatment of Neospora infections. BKI-1294 exposure of cell cultures infected with N. caninum tachyzoites results in the formation of massive multinucleated complexes (MNCs) containing numerous newly formed zoites, which remain viable for extended periods of time under drug pressure in vitro. MNC and tachyzoites exhibit considerable antigenic and structural differences. Methods: Using shotgun mass spectrometry, we compared the proteomes of tachyzoites to BKI-1294 induced MNCs, and analyzed the mRNA expression levels of selected genes in both stages. Results: More than half of the identified proteins are downregulated in MNCs as compared to tachyzoites. Only 12 proteins are upregulated, the majority of them containing SAG1 related sequence (SRS) domains, and some also known to be expressed in bradyzoites Conclusions: MNCs exhibit a proteome different from tachyzoites, share some bradyzoite-like features, but may constitute a third stage, which remains viable and ensures survival under adverse conditions such as drug pressure. We propose the term “baryzoites” for this stage (from Greek βα%υσ = massive, bulky, heavy, inert).


Item Type:Article
Uncontrolled Keywords:antigenic variation; chemotherapy; drug adaptation; drug resistance
Subjects:Medical sciences > Veterinary > Cattle
Medical sciences > Veterinary > Parasitology
ID Code:65099
Deposited On:26 Apr 2021 15:17
Last Modified:27 Apr 2021 07:13

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