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...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-11-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001197&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849695255266328576 |
|---|---|
| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-0f8218ee45454ff3ab2777fd18e7e8fc |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-0f8218ee45454ff3ab2777fd18e7e8fc2025-08-20T03:19:50ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-11-01611e100119710.1371/journal.ppat.1001197TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.Marie ChaussepiedNatacha JanskiMartin BaumgartnerRegina LizundiaKirsty JensenWilliam WeirBrian R ShielsJonathan B WeitzmanElizabeth J GlassDirk WerlingGordon LangsleyTheileria 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001197&type=printable |
| spellingShingle | 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. PLoS Pathogens |
| title | 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_short | 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 |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001197&type=printable |
| 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 |