TGF-b2 induction regulates invasiveness of theileria-transformed leukocytes and disease susceptibility

Chaussepied, M. et al. (2010) TGF-b2 induction regulates invasiveness of theileria-transformed leukocytes and disease susceptibility. PLoS Pathogens, 6(11), e1001197. (doi:10.1371/journal.ppat.1001197) (PMID:21124992) (PMCID:PMC2987823)

Chaussepied, M. et al. (2010) TGF-b2 induction regulates invasiveness of theileria-transformed leukocytes and disease susceptibility. PLoS Pathogens, 6(11), e1001197. (doi:10.1371/journal.ppat.1001197) (PMID:21124992) (PMCID:PMC2987823)

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Abstract

Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva), or tropical theileriosis (T. annulata). Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF) cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK). We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence.

Item Type:Articles
Additional Information:This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Weir, Dr William and Shiels, Professor Brian
Authors: Chaussepied, M., Janski, N., Baumgartner, M., Lizundia, R., Jensen, K., Weir, W., Shiels, B.R., Weitzman, J.B., Glass, E.J., Werling, D., Langsley, G., and Heussler, V.T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:18 November 2010
Copyright Holders:© 2010 Chaussepied et al
First Published:First published in PLoS Pathogens 2010 6(11): e1001197
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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