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

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 facto...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Marie Chaussepied, Natacha Janski, Martin Baumgartner, Regina Lizundia, Kirsty Jensen, William Weir, Brian R Shiels, Jonathan B Weitzman, Elizabeth J Glass, Dirk Werling, Gordon Langsley
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2010
Materias:
Acceso en línea:https://doaj.org/article/0f8218ee45454ff3ab2777fd18e7e8fc
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:0f8218ee45454ff3ab2777fd18e7e8fc
record_format dspace
spelling oai:doaj.org-article:0f8218ee45454ff3ab2777fd18e7e8fc2021-11-18T06:05:17ZTGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.1553-73661553-737410.1371/journal.ppat.1001197https://doaj.org/article/0f8218ee45454ff3ab2777fd18e7e8fc2010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21124992/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Theileria 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.Marie ChaussepiedNatacha JanskiMartin BaumgartnerRegina LizundiaKirsty JensenWilliam WeirBrian R ShielsJonathan B WeitzmanElizabeth J GlassDirk WerlingGordon LangsleyPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 11, p e1001197 (2010)
institution DOAJ
collection DOAJ
language EN
topic Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
spellingShingle Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
Marie Chaussepied
Natacha Janski
Martin Baumgartner
Regina Lizundia
Kirsty Jensen
William Weir
Brian R Shiels
Jonathan B Weitzman
Elizabeth J Glass
Dirk Werling
Gordon Langsley
TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.
description 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.
format article
author Marie Chaussepied
Natacha Janski
Martin Baumgartner
Regina Lizundia
Kirsty Jensen
William Weir
Brian R Shiels
Jonathan B Weitzman
Elizabeth J Glass
Dirk Werling
Gordon Langsley
author_facet Marie Chaussepied
Natacha Janski
Martin Baumgartner
Regina Lizundia
Kirsty Jensen
William Weir
Brian R Shiels
Jonathan B Weitzman
Elizabeth J Glass
Dirk Werling
Gordon Langsley
author_sort Marie Chaussepied
title TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.
title_short TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.
title_full TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.
title_fullStr TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.
title_full_unstemmed TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.
title_sort tgf-b2 induction regulates invasiveness of theileria-transformed leukocytes and disease susceptibility.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/0f8218ee45454ff3ab2777fd18e7e8fc
work_keys_str_mv AT mariechaussepied tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT natachajanski tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT martinbaumgartner tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT reginalizundia tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT kirstyjensen tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT williamweir tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT brianrshiels tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT jonathanbweitzman tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT elizabethjglass tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT dirkwerling tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
AT gordonlangsley tgfb2inductionregulatesinvasivenessoftheileriatransformedleukocytesanddiseasesusceptibility
_version_ 1718424585367453696