TLR Signaling Is Required for Salmonella typhimurium Virulence

被引:199
作者
Arpaia, Nicholas [1 ]
Godec, Jernej [1 ]
Lau, Laura [1 ]
Sivick, Kelsey E. [1 ]
McLaughlin, Laura M. [2 ]
Jones, Marcus B. [3 ]
Dracheva, Tatiana [3 ]
Peterson, Scott N. [3 ]
Monack, Denise M. [2 ]
Barton, Gregory M. [1 ]
机构
[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol & Pathogenesis, Berkeley, CA 94720 USA
[2] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA
[3] J Craig Venter Inst, Pathogen Funct Genom Resource Ctr, Rockville, MD 20850 USA
关键词
TOLL-LIKE RECEPTORS; III SECRETION SYSTEM; PATHOGENICITY ISLAND 2; PHAGOSOME MATURATION; SEROVAR TYPHIMURIUM; NATURAL-RESISTANCE; DENDRITIC CELLS; INTRACELLULAR PARASITES; ANTIMICROBIAL PEPTIDES; MACROPHAGE APOPTOSIS;
D O I
10.1016/j.cell.2011.01.031
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
Toll-like receptors (TLRs) contribute to host resistance to microbial pathogens and can drive the evolution of virulence mechanisms. We have examined the relationship between host resistance and pathogen virulence using mice with a functional allele of the nramp-1 gene and lacking combinations of TLRs. Mice deficient in both TLR2 and TLR4 were highly susceptible to the intracellular bacterial pathogen Salmonella typhimurium, consistent with reduced innate immune function. However, mice lacking additional TLRs involved in S. typhimurium recognition were less susceptible to infection. In these TLR-deficient cells, bacteria failed to upregulate Salmonella pathogenicity island 2 (SPI-2) genes and did not form a replicative compartment. We demonstrate that TLR signaling enhances the rate of acidification of the Salmonella-containing phagosome, and inhibition of this acidification prevents SPI-2 induction. Our results indicate that S. typhimurium requires cues from the innate immune system to regulate virulence genes necessary for intracellular survival, growth, and systemic infection.
引用
收藏
页码:675 / 688
页数:14
相关论文
共 72 条
[1]   Toll-like receptors: critical proteins linking innate and acquired immunity [J].
Akira, S ;
Takeda, K ;
Kaisho, T .
NATURE IMMUNOLOGY, 2001, 2 (08) :675-680
[2]   A Signaling Protease Required for Melanization in Drosophila Affects Resistance and Tolerance of Infections [J].
Ayres, Janelle S. ;
Schneider, David S. .
PLOS BIOLOGY, 2008, 6 (12) :2764-2773
[3]   Recognition of antimicrobial peptides by a bacterial sensor kinase [J].
Bader, MW ;
Sanowar, S ;
Daley, ME ;
Schneider, AR ;
Cho, US ;
Xu, WQ ;
Klevit, RE ;
Le Moual, H ;
Miller, S .
CELL, 2005, 122 (03) :461-472
[4]   TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis [J].
Bafica, A ;
Scanga, CA ;
Feng, CG ;
Leifer, C ;
Cheever, A ;
Sher, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (12) :1715-1724
[5]   Variations in the Nrampi gene and susceptibility to tuberculosis in West Africans [J].
Bellamy, R ;
Ruwende, C ;
Corrah, T ;
McAdam, KPWJ ;
Whittle, HC ;
Hill, AVS .
NEW ENGLAND JOURNAL OF MEDICINE, 1998, 338 (10) :640-644
[6]   Salmonella maintains the integrity of its intracellular vacuole through the action of SifA [J].
Beuzón, CR ;
Méresse, S ;
Unsworth, KE ;
Ruíz-Albert, J ;
Garvis, S ;
Waterman, SR ;
Ryder, TA ;
Boucrot, E ;
Holden, DW .
EMBO JOURNAL, 2000, 19 (13) :3235-3249
[7]   On regulation of phagosome maturation and antigen presentation [J].
Blander, J. Magarian ;
Medzhitov, Ruslan .
NATURE IMMUNOLOGY, 2006, 7 (10) :1029-1035
[8]   Regulation of phagosome maturation by signals from Toll-like receptors [J].
Blander, JM ;
Medzhitov, R .
SCIENCE, 2004, 304 (5673) :1014-1018
[9]   Toll-dependent selection of microbial antigens for presentation by dendritic cells [J].
Blander, JM ;
Medzhitov, R .
NATURE, 2006, 440 (7085) :808-812
[10]   Formation of a novel surface structure encoded by Salmonella Pathogenicity Island 2 [J].
Chakravortty, D ;
Rohde, M ;
Jäger, L ;
Deiwick, J ;
Hensel, M .
EMBO JOURNAL, 2005, 24 (11) :2043-2052