Muc5ac: a critical component mediating the rejection of enteric nematodes

被引:226
作者
Hasnain, Sumaira Z. [1 ,2 ]
Evans, Christopher M. [3 ]
Roy, Michelle [3 ]
Gallagher, Amanda L. [2 ]
Kindrachuk, Kristen N. [4 ]
Barron, Luke [4 ]
Dickey, Burton F. [3 ]
Wilson, Mark S. [5 ]
Wynn, Thomas A. [4 ]
Grencis, Richard K. [2 ]
Thornton, David J. [1 ]
机构
[1] Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
[2] Univ Manchester, Manchester Immunol Grp, Fac Life Sci, Manchester M13 9PT, Lancs, England
[3] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA
[4] NIAID, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA
[5] Natl Inst Med Res, Div Mol Immunol, Med Res Council, London NW7 1AA, England
基金
美国国家卫生研究院; 英国惠康基金; 英国生物技术与生命科学研究理事会;
关键词
MUCIN GENE-EXPRESSION; ABNORMAL EXPRESSION; MUCUS; INFECTIONS; BARRIER; ALPHA; COLON; MICE;
D O I
10.1084/jem.20102057
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
De novo expression of Muc5ac, a mucin not normally expressed in the intestinal tract, is induced in the cecum of mice resistant to Trichuris muris infection. In this study, we investigated the role of Muc5ac, which is detected shortly before worm expulsion and is associated with the production of interleukin-13 (IL-13), in resistance to this nematode. Muc5ac-deficient mice were incapable of expelling T. muris from the intestine and harbored long-term chronic infections, despite developing strong T(H)2 responses. Muc5ac-deficient mice had elevated levels of IL-13 and, surprisingly, an increase in the T(H)1 cytokine IFN-gamma. Because T(H)1 inflammation is thought to favor chronic nematode infection, IFN-gamma was neutralized in vivo, resulting in an even stronger T(H)2-type immune response. Nevertheless, despite a more robust T(H)2 effector response, the Muc5ac-deficient mice remained highly susceptible to chronic T. muris infection. Importantly, human MUC5AC had a direct detrimental effect on nematode vitality. Moreover, the absence of Muc5ac caused a significant delay in the expulsion of two other gut-dwelling nematodes (Trichinella spiralis and Nippostrongylus brasiliensis). Thus, for the first time, we identify a single mucin, Muc5ac, as a direct and critical mediator of resistance during intestinal nematode infection.
引用
收藏
页码:893 / 900
页数:8
相关论文
共 31 条
[1]  
Andrianifahanana M, 2001, CLIN CANCER RES, V7, P4033
[2]   The intestinal epithelium: sensors to effectors in nematode infection [J].
Artis, D. ;
Grencis, R. K. .
MUCOSAL IMMUNOLOGY, 2008, 1 (04) :252-264
[3]   Abnormal expression of gastric mucin in human and rat aberrant crypt foci during colon carcinogenesis [J].
Bara, J ;
Forgue-Lafitte, ME ;
Maurin, N ;
Fléjou, JF ;
Zimber, A .
TUMOR BIOLOGY, 2003, 24 (03) :109-115
[4]   IMMUNOLOGICAL RELATIONSHIPS DURING PRIMARY INFECTION WITH HELIGMOSOMOIDES-POLYGYRUS (NEMATOSPIROIDES-DUBIUS) - DOWN-REGULATION OF SPECIFIC CYTOKINE SECRETION (IL-9 AND IL-10) CORRELATES WITH POOR MASTOCYTOSIS AND CHRONIC SURVIVAL OF ADULT WORMS [J].
BEHNKE, JM ;
WAHID, FN ;
GRENCIS, RK ;
ELSE, KJ ;
BENSMITH, AW ;
GOYAL, PK .
PARASITE IMMUNOLOGY, 1993, 15 (07) :415-421
[5]   Mucin gene expression in human embryonic and fetal intestine [J].
Buisine, MP ;
Devisme, L ;
Savidge, TC ;
Gespach, C ;
Gosselin, B ;
Porchet, N ;
Aubert, JP .
GUT, 1998, 43 (04) :519-524
[6]  
Camberis Mali, 2003, Curr Protoc Immunol, VChapter 19, DOI 10.1002/0471142735.im1912s55
[7]   THE MACROMOLECULAR STRUCTURE OF HUMAN CERVICAL-MUCUS GLYCOPROTEINS - STUDIES ON FRAGMENTS OBTAINED AFTER REDUCTION OF DISULFIDE BRIDGES AND AFTER SUBSEQUENT TRYPSIN DIGESTION [J].
CARLSTEDT, I ;
LINDGREN, H ;
SHEEHAN, JK .
BIOCHEMICAL JOURNAL, 1983, 213 (02) :427-435
[8]   Accelerated intestinal epithelial cell turnover: A new mechanism of parasite expulsion [J].
Cliffe, LJ ;
Humphreys, NE ;
Lane, TE ;
Potten, CS ;
Booth, C ;
Grencis, RK .
SCIENCE, 2005, 308 (5727) :1463-1465
[9]   The Trichuris muris system:: a paradigm of resistance and susceptibility to intestinal nematode infection [J].
Cliffe, LJ ;
Grencis, RK .
ADVANCES IN PARASITOLOGY, VOL 57, 2004, 57 :255-307
[10]  
Deplancke B, 2001, AM J CLIN NUTR, V73, p1131S