Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine

被引：713

作者：

Cadwell, Ken ^{[1
]}

Patel, Khushbu K. ^{[1
]}

Maloney, Nicole S. ^{[1
]}

Liu, Ta-Chiang ^{[1
]}

Ng, Aylwin C. Y. ^{[3
,4
,5
,6
]}

Storer, Chad E. ^{[7
]}

Head, Richard D. ^{[7
]}

Xavier, Ramnik ^{[3
,4
,5
,6
]}

Stappenbeck, Thaddeus S. ^{[1
]}

Virgin, Herbert W. ^{[1
,2
,8
]}

机构：

[1] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA

[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA

[4] Harvard Univ, Ctr Computat & Integrat Biol, Sch Med, Boston, MA 02114 USA

[5] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[6] Harvard Univ, Cambridge, MA 02142 USA

[7] Pfizer Global Res & Dev, Inflammat & Immunol Res Unit, St Louis, MO 63017 USA

[8] Midwest Reg Ctr Excellence Biodefense & Emerging, St Louis, MO 63110 USA

来源：

CELL | 2010年 / 141卷 / 07期

关键词：

GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; MURINE NOROVIRUS; MURINE-NOROVIRUS-1; INFECTION; MONOCLONAL-ANTIBODIES; INFLUENZA-VIRUS; CELIAC-DISEASE; MOUSE MODEL; IN-VITRO; KEY ROLE;

D O I：

10.1016/j.cell.2010.05.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

It is unclear why disease occurs in only a small proportion of persons carrying common risk alleles of disease susceptibility genes. Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn's disease susceptibility gene Atg16L1 induces intestinal pathologies in mice. This virus-plus-susceptibility gene interaction generated abnormalities in granule packaging and unique patterns of gene expression in Paneth cells. Further, the response to injury induced by the toxic substance dextran sodium sulfate was fundamentally altered to include pathologies resembling aspects of Crohn's disease. These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNF alpha and IFN gamma and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype of hosts carrying common risk alleles for inflammatory disease.

引用

页码：1135 / U64

页数：18

共 71 条

[1] ACUTE INFECTIOUS NONBACTERIAL GASTROENTERITIS - INTESTINAL HISTOPATHOLOGY - HISTOLOGIC AND ENZYMATIC ALTERATIONS DURING ILLNESS PRODUCED BY NORWALK AGENT IN MAN [J].

AGUS, SG ;

DOLIN, R ;

WYATT, RG ;

TOUSIMIS, AJ ;

NORTHRUP, RS .

ANNALS OF INTERNAL MEDICINE, 1973, 79 (01) :18-25

[2] Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease [J].

Alberto, Luis ;

Rodriguez, Garcia ;

Ruigomez, Ana ;

Panes, Julian .

GASTROENTEROLOGY, 2006, 130 (06) :1588-1594

[3] Genetic Mapping in Human Disease [J].

Altshuler, David ;

Daly, Mark J. ;

Lander, Eric S. .

SCIENCE, 2008, 322 (5903) :881-888

[4] Effects of Acute and Chronic Murine Norovirus Infections on Immune Responses and Recovery from Friend Retrovirus Infection [J].

Ammann, Christoph G. ;

Messer, Ronald J. ;

Varvel, Kimberly ;

DeBuysscher, Blair L. ;

LaCasse, Rachel A. ;

Pinto, Amelia K. ;

Hasenkrug, Kim J. .

JOURNAL OF VIROLOGY, 2009, 83 (24) :13037-13041

[5] Regulatory T Cells Reinforce Intestinal Homeostasis [J].

Barnes, Michael J. ;

Powrie, Fiona .

IMMUNITY, 2009, 31 (03) :401-411

[6] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[7] Macrophages driven to a novel state of activation have anti-inflammatory properties in mice [J].

Brem-Exner, Beate G. ;

Sattler, Christine ;

Hutchinson, James A. ;

Koehl, Gudrun E. ;

Kronenberg, Katharina ;

Farkas, Stefan ;

Inoue, Seiichiro ;

Blank, Christian ;

Knechtle, Stuart J. ;

Schlitt, Hans J. ;

Faendrich, Fred ;

Geissler, Edward K. .

JOURNAL OF IMMUNOLOGY, 2008, 180 (01) :335-349

[8] Microbial translocation is a cause of systemic immune activation in chronic HIV infection [J].

Brenchley, Jason M. ;

Price, David A. ;

Schacker, Timothy W. ;

Asher, Tedi E. ;

Silvestri, Guido ;

Rao, Srinivas ;

Kazzaz, Zachary ;

Bornstein, Ethan ;

Lambotte, Olivier ;

Altmann, Daniel ;

Blazar, Bruce R. ;

Rodriguez, Benigno ;

Teixeira-Johnson, Leia ;

Landay, Alan ;

Martin, Jeffrey N. ;

Hecht, Frederick M. ;

Picker, Louis J. ;

Lederman, Michael M. ;

Deeks, Steven G. ;

Douek, Daniel C. .

NATURE MEDICINE, 2006, 12 (12) :1365-1371

[9] IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells [J].

Brockman, Mark A. ;

Kwon, Douglas S. ;

Tighe, Daniel P. ;

Pavlik, David F. ;

Rosato, Pamela C. ;

Sela, Jennifer ;

Porichis, Filippos ;

Le Gall, Sylvie ;

Waring, Michael T. ;

Moss, Kristin ;

Jessen, Heiko ;

Pereyra, Florencia ;

Kavanagh, Daniel G. ;

Walker, Bruce D. ;

Kaufmann, Daniel E. .

BLOOD, 2009, 114 (02) :346-356

[10] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

← 1 2 3 4 5 6 7 8 →