Helminth cysteine proteases inhibit TRIF-dependent activation of macrophages via degradation of TLR3.
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.
Donnelly
Sheila
S
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.
O'Neill
Sandra M
SM
Stack
Colin M
CM
Robinson
Mark W
MW
Turnbull
Lynne
L
Whitchurch
Cynthia
C
Dalton
John P
JP
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D057056:Cysteine Proteases / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000737:chemistry; D005260:Female; D006376:Helminths; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D018417:Th1 Cells / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000737:chemistry*
D033942:Adaptor Proteins, Vesicular Transport; D057056:Cysteine Proteases; D016207:Cytokines; D004731:Endotoxins; D053594:Myeloid Differentiation Factor 88; D009573:Nitrites; D011994:Recombinant Proteins; D051196:Toll-Like Receptor 3; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse