Genetic and Physical Mapping of theLpsLocus: Identification of the Toll-4 Receptor as a Candidate Gene in the Critical Region

Poltorak, Alexander; Smirnova, I.; He, Xiaolong; Liu, Mu Ya; Huffel, Christophe Van; Birdwell, Dale; Alejos, E.; Silva, Maria João; Du, Xin; Thompson, Patricia A.; Chan, Edward K. L.; Ledesma, Jessica; Roe, Bruce A.; Clifton, Sandra W.; Vogel, Stefanie N.; Beutler, Bruce

doi:10.1006/bcmd.1998.0201

Cited by 394 publications

(255 citation statements)

References 15 publications

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“…74,82 Early linkage analysis studies revealed that Lps cosegregated with the major urinary protein locus (Mup-1) and the polysyndactyly (Ps) mutation indicating that Lps is located on mouse chromosome 4. 80,81 Highresolution genetic, physical and transcriptional maps of the area were thereafter generated 82,83 and led to the identification of Tlr4 as a candidate for Lps. 83,84 Three different Tlr4 mutant alleles were identified: C3H/HeJ mice present a single missense mutation resulting in a proline for histidine substitution at codon 712 within the signaling domain; 84,85 in C57BL/10ScCr mice, there were no Tlr4 transcripts detected 84,85 as a consequence of a 75 kb chromosomal deletion encompassing the whole Tlr4 gene; 86 the mutation identified in C57BL/6.KB2-mnd Tlr4 consists in a complete deletion of exon II.…”

Section: Tlr4mentioning

confidence: 99%

Genetic regulation of host responses to Salmonella infection in mice

Malo

2002

Genes Immun

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Salmonella spp are Gram-negative bacteria capable of infecting a wide range of host species, including humans, domesticated and wild mammals, reptiles, birds and insects. The outcome of an encounter between Salmonella and its host is dependent upon multiple factors including the host genetic background. To facilitate the study of the genetic factors involved in resistance to this pathogen, mouse models of Salmonella infection have been developed and studied for years, allowing identification of several genes and pathways that may influence the disease outcome. In this review, we will cover some of the genes involved in mouse resistance to Salmonella that were identified through the study of congenic mouse strains, cloning of spontaneous mouse mutations, use of site-directed mutagenesis or quantitative trait loci analysis. In parallel, the relevant information pertaining to genes involved in resistance to Salmonella in humans will be discussed.

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Section: Tlr4mentioning

confidence: 99%

Genetic regulation of host responses to Salmonella infection in mice

Malo

2002

Genes Immun

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“…PAMPs include cell wall components derived from Gram-positive bacteria, LPS from Gramnegative bacteria, lipoteichoic acid, and flagellum, all of which are recognized by Toll-like receptors (TLRs). Specifically, bacterial cell wall components and lipoteichoic acid are recognized by TLR2 (Schwandner et al, 1999), and LPS and flagellin bind TLR4 and TLR5, respectively (Hayashi et al, 2001;Poltorak et al, 1998). Ligand binding by TLRs leads to the induction of immune and inflammatory genes (Akira & Takeda, 2004).…”

Section: Introductionmentioning

confidence: 99%

Salmonella virulence factor SpiC is involved in expression of flagellin protein and mediates activation of the signal transduction pathways in macrophages

Uchiya

Nikai

2008

Microbiology

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“…Later identification of the LPS gene through positional cloning (11) and production of TLR4 knockout mice confirmed that TLR4 (formerly known as the LPS locus) is needed to trigger the immune response to LPS (12)(13)(14). Those studies established that the signal-transducing receptor for LPS is TLR4.…”

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confidence: 99%

MHC Class II Molecules Control Murine B Cell Responsiveness to Lipopolysaccharide Stimulation

Rodo

Gonçalves

Demengeot

et al. 2006

The Journal of Immunology

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LPS is a strong stimulator of the innate immune system and inducer of B lymphocyte activation. Two TLRs, TLR4 and RP105 (CD180), have been identified as mediators of LPS signaling in murine B cells, but little is known about genetic factors that are able to control LPS-induced cell activation. We performed a mouse genome-wide screen that aside from identifying a controlling locus mapping in the TLR4 region (logarithm of odds score, 2.77), also revealed that a locus closely linked to the MHC region (logarithm of odds score, 3.4) governed B cell responsiveness to LPS stimulation. Using purified B cells obtained from MHC congenic strains, we demonstrated that the MHCb haplotype is accountable for higher cell activation, cell proliferation, and IgM secretion, after LPS stimulation, when compared with the MHCd haplotype. Furthermore, B cells from MHC class II−/− mice displayed enhanced activation and proliferation in response to LPS. In addition, we showed that the MHC haplotype partially controls expression of RP105 (a LPS receptor molecule), following a pattern that resembles the LPS responsiveness phenotype. Together, our results strongly suggest that murine MHC class II molecules play a role in constraining the B cell response to LPS and that genetic variation at the MHC locus is an important component in controlling B cell responsiveness to LPS stimulation. This work raises the possibility that constraining of B cell responsiveness by MHC class II molecules may represent a functional interaction between adaptive and innate immune systems.

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Genetic and Physical Mapping of theLpsLocus: Identification of the Toll-4 Receptor as a Candidate Gene in the Critical Region

Cited by 394 publications

References 15 publications

Genetic regulation of host responses to Salmonella infection in mice

Genetic regulation of host responses to Salmonella infection in mice

Salmonella virulence factor SpiC is involved in expression of flagellin protein and mediates activation of the signal transduction pathways in macrophages

MHC Class II Molecules Control Murine B Cell Responsiveness to Lipopolysaccharide Stimulation

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