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Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3
Sheila Donnelly1,
Sandra M. O'Neill¶,
Colin M. Stack||,
Mark W. Robinson,
Lynne Turnbull,
Cynthia Whitchurch, , and
John P. Dalton**
From the 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:
Helminth pathogens prepare a Th2 type immunological environmentin their hosts to ensure their longevity. They achieve thisby secreting molecules that not only actively drive type 2 responsesbut also suppress type 1 responses. Here, we show that the majorcysteine proteases secreted from the helminth pathogens Fasciolahepatica (FheCL1) and Schistosoma mansoni (SmCB1) protect micefrom the lethal effects of lipopolysaccharide by preventingthe release of inflammatory mediators, nitric oxide, interleukin-6,tumor necrosis factor , and interleukin-12, from macrophages.The proteases specifically block the MyD88-independent TRIF-dependentsignaling pathway of Toll-like receptor (TLR)4 and TLR3. Microscopicaland flow cytometric studies, however, show that alteration ofmacrophage function by cysteine protease is not mediated bycleavage of components of the TLR4 complex on the cell surfacebut occurs by degradation of TLR3 within the endosome. Thisis the first study to describe a parasite molecule that degradesthis receptor and pinpoints a novel mechanism by which helminthparasites modulate the innate immune responses of their hoststo suppress the development of Th1 responses.
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}nuim.ie.
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1,
Sandra M. O'Neill¶,
Colin M. Stack
, 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. 
