Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3

被引:122
作者
Donnelly, Sheila [1 ]
O'Neill, Sandra M. [3 ]
Stack, Colin M. [4 ]
Robinson, Mark W.
Turnbull, Lynne
Whitchurch, Cynthia
Dalton, John P. [2 ,5 ]
机构
[1] Natl Univ Ireland Maynooth, Dept Biol, Maynooth, Kildare, Ireland
[2] Univ Technol Sydney, Inst Biotechnol Infect Dis, Sydney, NSW 2007, Australia
[3] Dublin City Univ, Sch Nursing, Dublin 9, Ireland
[4] Univ Western Sydney, Sch Biomed & Hlth Sci, Campbelltown, NSW 2560, Australia
[5] McGill Univ, Inst Parasitol, Ste Anne De Bellevue, PQ H9X 3V9, Canada
关键词
IFN-BETA PROMOTER; FASCIOLA-HEPATICA; LIVER FLUKE; BORDETELLA-PERTUSSIS; MEDIATED CLEAVAGE; IMMUNE EVASION; CATHEPSIN L1; LIPOPOLYSACCHARIDE; PROTEINASES; INFECTION;
D O I
10.1074/jbc.M109.060368
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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.
引用
收藏
页码:3383 / 3392
页数:10
相关论文
共 46 条
[1]
Ordered recruitment of chromatin modifying and general transcription factors to the IFN-β promoter [J].
Agalioti, T ;
Lomvardas, S ;
Parekh, B ;
Yie, JM ;
Maniatis, T ;
Thanos, D .
CELL, 2000, 103 (04) :667-678
[2]
Toll-like receptor signalling [J].
Akira, S ;
Takeda, K .
NATURE REVIEWS IMMUNOLOGY, 2004, 4 (07) :499-511
[3]
IRF-3-dependent and augmented target genes during viral infection [J].
Andersen, J. ;
VanScoy, S. ;
Cheng, T-F ;
Gomez, D. ;
Reich, N. C. .
GENES AND IMMUNITY, 2008, 9 (02) :168-175
[4]
IL-4R signaling is required to induce IL-10 for the establishment of Th2 dominance [J].
Balic, Adam ;
Harcus, Yvonne M. ;
Taylor, Matthew D. ;
Brombacher, Frank ;
Maizels, Rick M. .
INTERNATIONAL IMMUNOLOGY, 2006, 18 (10) :1421-1431
[5]
Fasciola hepatica:: Parasite-secreted proteinases degrade all human IgG subclasses:: Determination of the specific cleavage sites and identification of the immunoglobulin fragments produced [J].
Berasain, P ;
Carmona, C ;
Frangione, B ;
Dalton, JP ;
Goñi, F .
EXPERIMENTAL PARASITOLOGY, 2000, 94 (02) :99-110
[6]
Fasciola hepatica suppresses a protective Th1 response against Bordetella pertussis [J].
Brady, MT ;
O'Neill, SM ;
Dalton, JP ;
Mills, KHG .
INFECTION AND IMMUNITY, 1999, 67 (10) :5372-5378
[7]
The Schistosoma mansoni Protein Sm16/SmSLP/SmSPO-1 Assembles into a Nine-Subunit Oligomer with Potential To Inhibit Toll-Like Receptor Signaling [J].
Brannstrom, Kristoffer ;
Sellin, Mikael E. ;
Holmfeldt, Per ;
Brattsand, Maria ;
Gullberg, Martin .
INFECTION AND IMMUNITY, 2009, 77 (03) :1144-1154
[8]
Review series on helminths, immune modulation and the hygiene hypothesis: Mechanisms underlying helminth modulation of dendritic cell function [J].
Carvalho, Lucas ;
Sun, Jie ;
Kane, Colleen ;
Marshall, Fraser ;
Krawczyk, Connie ;
Pearce, Edward J. .
IMMUNOLOGY, 2009, 126 (01) :28-34
[9]
TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events [J].
Cavassani, Karen A. ;
Ishii, Makoto ;
Wen, Haitao ;
Schaller, Matthew A. ;
Lincoln, Pamela M. ;
Lukacs, Nicholas W. ;
Hogaboam, Cory M. ;
Kunkel, Steven L. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2008, 205 (11) :2609-2621
[10]
Cathepsin L1, the major protease involved in liver fluke (Fasciola hepatica) virulence -: Propeptide cleavage sites and autoactivation of the zymogen secreted from gastrodermal cells [J].
Collins, PR ;
Stack, CM ;
O'Neill, SM ;
Doyle, S ;
Ryan, T ;
Brennan, GP ;
Mousley, A ;
Stewart, M ;
Maule, AG ;
Dalton, JP ;
Donnelly, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (17) :17038-17046