Pathogen Specific, IRF3-Dependent Signaling and Innate Resistance to Human Kidney Infection

被引:51
作者
Fischer, Hans [1 ]
Lutay, Nataliya [1 ]
Ragnarsdottir, Bryndis [1 ]
Yadav, Manisha [1 ]
Joensson, Klas [2 ]
Urbano, Alexander [2 ]
Al Hadad, Ahmed [1 ]
Ramisch, Sebastian [1 ]
Storm, Petter [1 ]
Dobrindt, Ulrich [3 ]
Salvador, Ellaine [3 ]
Karpman, Diana [4 ,5 ]
Jodal, Ulf [6 ]
Svanborg, Catharina [1 ,2 ]
机构
[1] Lund Univ, Inst Lab Med, Dept Microbiol Immunol & Glycobiol, Lund, Sweden
[2] ASTAR, Inst Biomed Sci, Singapore Immunol Network SIgN, Singapore, Singapore
[3] Julius Maximilians Univ, Inst Mol Biol Infect Dis, Wurzburg, Germany
[4] Lund Univ, Dept Pediat, Lund, Sweden
[5] Univ Lund Hosp, S-22185 Lund, Sweden
[6] Univ Gothenburg, Queen Silvia Childrens Hosp, Pediat Uronephrol Ctr, Gothenburg, Sweden
基金
英国医学研究理事会;
关键词
UROPATHOGENIC ESCHERICHIA-COLI; URINARY-TRACT-INFECTION; NF-KAPPA-B; ASYMPTOMATIC BACTERIURIA; ACUTE PYELONEPHRITIS; HOST-DEFENSE; P-FIMBRIAE; RECOGNITION RECEPTORS; REGULATORY FACTOR-3; CYTOKINE RESPONSES;
D O I
10.1371/journal.ppat.1001109
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFN beta-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3(-/-) mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response.
引用
收藏
页数:17
相关论文
共 72 条
[1]   Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus [J].
Akahoshi, M. ;
Nakashima, H. ;
Sadanaga, A. ;
Miyake, K. ;
Obara, K. ;
Tamari, M. ;
Hirota, T. ;
Matsuda, A. ;
Shirakawa, T. .
LUPUS, 2008, 17 (06) :568-574
[2]   FimH Adhesin of Type 1 Fimbriae Is a Potent Inducer of Innate Antimicrobial Responses Which Requires TLR4 and Type 1 Interferon Signalling [J].
Ashkar, Ali A. ;
Mossman, Karen L. ;
Coombes, Brian K. ;
Gyles, Carlton L. ;
Mackenzie, Randy .
PLOS PATHOGENS, 2008, 4 (12)
[3]  
Astarie-Dequeker C, 2002, J CELL SCI, V115, P81
[4]   IDENTIFICATION OF A MEMBER OF THE INTERFERON REGULATORY FACTOR FAMILY THAT BINDS TO THE INTERFERON-STIMULATED RESPONSE ELEMENT AND ACTIVATES EXPRESSION OF INTERFERON-INDUCED GENES [J].
AU, WC ;
MOORE, PA ;
LOWTHER, W ;
JUANG, YT ;
PITHA, PM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (25) :11657-11661
[5]   Ceramide signalling and the immune response [J].
Ballou, LR ;
Laulederkind, SJF ;
Rosloniec, EF ;
Raghow, R .
BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM, 1996, 1301 (03) :273-287
[6]   The molecular structure of the Toll-like receptor 3 ligand-binding domain [J].
Bell, JK ;
Botos, I ;
Hall, PR ;
Askins, J ;
Shiloach, J ;
Segal, DM ;
Davies, DR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (31) :10976-10980
[7]   Guanylyl cyclase C as a reliable immunohistochemical marker and its ligand Escherichia coli heat-stable enterotoxin as a potential protein-delivering vehicle for colorectal cancer cells [J].
Buc, E ;
Der Vartanian, M ;
Darcha, C ;
Déchelotte, P ;
Pezet, D .
EUROPEAN JOURNAL OF CANCER, 2005, 41 (11) :1618-1627
[8]   Hemoglobin E:: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria [J].
Chotivanich, K ;
Udomsangpetch, R ;
Pattanapanyasat, K ;
Chierakul, W ;
Simpson, J ;
Looareesuwan, S ;
White, N .
BLOOD, 2002, 100 (04) :1172-1176
[9]   PHOSPHORYLATED CREB BINDS SPECIFICALLY TO THE NUCLEAR-PROTEIN CBP [J].
CHRIVIA, JC ;
KWOK, RPS ;
LAMB, N ;
HAGIWARA, M ;
MONTMINY, MR ;
GOODMAN, RH .
NATURE, 1993, 365 (6449) :855-859
[10]   A novel normalization method for effective removal of systematic variation in microarray data [J].
Chua, SW ;
Vijayakumar, P ;
Nissom, PM ;
Yam, CY ;
Wong, VVT ;
Yang, H .
NUCLEIC ACIDS RESEARCH, 2006, 34 (05)