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J. Biol. Chem. 285 (5): 3383-3392

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3Formula

Sheila Donnelly{ddagger}§1, Sandra M. O'Neill, Colin M. Stack{ddagger}||, Mark W. Robinson{ddagger}, Lynne Turnbull{ddagger}, Cynthia Whitchurch{ddagger}, , and John P. Dalton{ddagger}**

From the {ddagger}Institute for the Biotechnology of Infectious Diseases, University of Technology Sydney, Level 6, Building 4, Corner of Thomas and Harris Street, Ultimo, Sydney, New South Wales 2007, Australia,
the §Department of Biology, National University of Ireland Maynooth, County Kildare, Ireland,
the School of Nursing, Dublin City University, Glasnevin, Dublin 9, Ireland,
the ||School of Biomedical and Health Sciences, University of Western Sydney, Narellan Road, Campbelltown, New South Wales 2560, Australia, and
the **Institute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec H9X 3V9, Canada

ABSTRACT Back to Top

Abstract: Helminth pathogens prepare a Th2 type immunological environment in their hosts to ensure their longevity. They achieve this by secreting molecules that not only actively drive type 2 responses but also suppress type 1 responses. Here, we show that the major cysteine proteases secreted from the helminth pathogens Fasciola hepatica (FheCL1) and Schistosoma mansoni (SmCB1) protect mice from the lethal effects of lipopolysaccharide by preventing the release of inflammatory mediators, nitric oxide, interleukin-6, tumor necrosis factor {alpha}, and interleukin-12, from macrophages. The proteases specifically block the MyD88-independent TRIF-dependent signaling pathway of Toll-like receptor (TLR)4 and TLR3. Microscopical and flow cytometric studies, however, show that alteration of macrophage function by cysteine protease is not mediated by cleavage of components of the TLR4 complex on the cell surface but occurs by degradation of TLR3 within the endosome. This is the first study to describe a parasite molecule that degrades this receptor and pinpoints a novel mechanism by which helminth parasites modulate the innate immune responses of their hosts to suppress the development of Th1 responses.

Key Words: Enzymes/Peptidases • Immunology/Innate Immunity • Immunology/Toll Receptors • Organisms/Parasite • Parasitology • Proteases/Cysteine Protease

Received for publication August 27, 2009.

1 To whom correspondence should be addressed: Department of Biology, National University of Ireland Maynooth, County Kildare, Ireland. Tel.: 353-1-7086845; Fax: 353-1-7083845; E-mail: sheila.donnelly{at}

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