TGF-b2 Induction Regulates Invasiveness of Theileria-Transformed Leukocytes and Disease Susceptibility

PLoS Pathogens

Regina Lizundia¹  Elizabeth J. Glass²  Gordon Langsley³  Dirk Werling³  Natacha Janski⁴  Brian R. Shiels⁴  Marie Chaussepied⁵  William Weir⁵  Jonathan B. Weitzman⁶  Kirsty Jensen⁷  Martin Baumgartner⁸ 

[1] CNRS UMR7216 Epigénétique et Destin Cellulaire, Paris, France;Division of Genetics and Genomics, The Roslin Institute and Royal Dick School of Veterinary Studies, The University of Edinburgh, Roslin, Midlothian, United Kingdom;Division of Veterinary Infection and Immunity, University of Glasgow, Faculty of Veterinary Medicine, Institute of Comparative Medicine, Bearsden Road, Glasgow, United Kingdom;Inserm U1016, Paris, France;Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France;Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, United Kingdom;University of Berne, Department of Clinical Research and Veterinary Public Health, Division Molecular Pathobiology, Bern, Switzerland;Université Paris-Diderot Paris 7, Paris, France

关键词: Macrophages;    White blood cells;    Theileria;    Parasitic diseases;    Actins;    Collagens;    Host cells;    RNA extraction;   

DOI  :  10.1371/journal.ppat.1001197

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY