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

1
Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, Mittelstrasse 43, 3012 Bern, Switzerland
3
Proteomics & Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Berne, Freiburgstrasse 15, CH-3010 Berne, Switzerland
4
Center for Emerging and Re-emerging Infectious Diseases (CERID), Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA
5
SALUVET, Animal Health Department, Faculty of Veterinary Sciences, Complutense University of Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Microorganisms 2020, 8(6), 801; https://doi.org/10.3390/microorganisms8060801
Received: 4 May 2020 / Revised: 21 May 2020 / Accepted: 23 May 2020 / Published: 26 May 2020
(This article belongs to the Section Public Health Microbiology)
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 βαρυσ = massive, bulky, heavy, inert). View Full-Text
Keywords: antigenic variation; chemotherapy; drug adaptation; drug resistance antigenic variation; chemotherapy; drug adaptation; drug resistance
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MDPI and ACS Style

Winzer, P.; Müller, J.; Imhof, D.; Ritler, D.; Uldry, A.-C.; Braga-Lagache, S.; Heller, M.; Ojo, K.K.; Van Voorhis, W.C.; Ortega-Mora, L.-M.; Hemphill, A. Neospora caninum: Differential Proteome of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294. Microorganisms 2020, 8, 801. https://doi.org/10.3390/microorganisms8060801

AMA Style

Winzer P, Müller J, Imhof D, Ritler D, Uldry A-C, Braga-Lagache S, Heller M, Ojo KK, Van Voorhis WC, Ortega-Mora L-M, Hemphill A. Neospora caninum: Differential Proteome of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294. Microorganisms. 2020; 8(6):801. https://doi.org/10.3390/microorganisms8060801

Chicago/Turabian Style

Winzer, Pablo, Joachim Müller, Dennis Imhof, Dominic Ritler, Anne-Christine Uldry, Sophie Braga-Lagache, Manfred Heller, Kayode K. Ojo, Wesley C. Van Voorhis, Luis-Miguel Ortega-Mora, and Andrew Hemphill. 2020. "Neospora caninum: Differential Proteome of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294" Microorganisms 8, no. 6: 801. https://doi.org/10.3390/microorganisms8060801

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