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

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. (2010). TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility. PLoS pathogens, 6(11), e1001197. San Francisco, Calif.: Public Library of Science 10.1371/journal.ppat.1001197

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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:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research

UniBE Contributor:

Baumgartner, Martin

ISSN:

1553-7366

Publisher:

Public Library of Science

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:35

Last Modified:

13 Aug 2015 13:57

Publisher DOI:

10.1371/journal.ppat.1001197

Web of Science ID:

000284586300030

BORIS DOI:

10.7892/boris.14206

URI:

https://boris.unibe.ch/id/eprint/14206 (FactScience: 221064)

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