Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes

Mf, Roy; Larivière, Line; Wilkinson, Rosalie; M, Tam; Mm, Stevenson; Malo, Danielle

doi:10.1038/sj.gene.6364309

Cited by 34 publications

(26 citation statements)

References 44 publications

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“…C57BL/6J and 129S6 mice are known to present different degrees of susceptibility to systemic Salmonella Typhimurium and Salmonella Enteritidis infections. 19,20 It is known that these two parental strains differ in their susceptibility to acute Salmonella Typhimurium infection because of NRAMP1, C57BL/6J mice carry a non-functional Nramp1 gene resulting in extreme susceptibility to infection. In addition, resistance to virulent Salmonella Typhimurium infection is rarely seen in inbred mouse strains with the exception of several 129 substrains including 129S6, 129X1 and 129S1 (Roy et al 19 and unpublished data).…”

Section: Resultsmentioning

confidence: 99%

“…19,20 It is known that these two parental strains differ in their susceptibility to acute Salmonella Typhimurium infection because of NRAMP1, C57BL/6J mice carry a non-functional Nramp1 gene resulting in extreme susceptibility to infection. In addition, resistance to virulent Salmonella Typhimurium infection is rarely seen in inbred mouse strains with the exception of several 129 substrains including 129S6, 129X1 and 129S1 (Roy et al 19 and unpublished data). On the other hand, systemic Salmonella enteritis infection in C57BL/6J and 129S6 does not cause clinical disease: the C57BL/6J mice are able to clear the bacteria from their reticuloendothelial system within a period of 6 weeks whereas 129S6 mice still present high bacterial load in the spleen and mesenteric lymph nodes 12 weeks post infection.…”

Section: Resultsmentioning

confidence: 99%

“…The importance of the IL-12/IFNg axis, TNF and IL-1 in the host response to Salmonella-induced typhoid is well known in mice [29][30][31] and increased expression of these genes have been reported by us in the spleen of Salmonella-infected mice. 19,20,32 Additional important effector genes were upregulated during infection in the cecum of Usp18 þ /Ity9 mice including Nramp1, Ncf4, Lcn2 and Ido1. Nramp1 is a pH-dependent manganese (Mn 2 þ ) and iron (Fe 2 þ ) efflux pump located at the phagosomal membrane that exerts an antimicrobial effect against several intracellular pathogens including Salmonella through its capacity to restrict the availability of metal ions from the phagosomal space (reviewed in Vidal et al 3 ).…”

Section: Discussionmentioning

confidence: 99%

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Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

et al. 2011

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In humans, Salmonella infection causes two major clinical diseases, typhoid fever and a self-limiting gastro-enteritidis. Salmonella transmission occurs by the fecal-oral route and the interactions between the bacteria and the digestive tract epithelium are central to the outcome of the infection. Using a mouse model of typhoid fever, we previously identified a mutation in USP18 affecting type I interferon (IFN) signaling resulting in increased susceptibility to systemic Salmonella infection. In this study, we demonstrate the effects of this mutation during the early response to Salmonella using a model of typhlitis. Mutant Usp18 mice showed a minimal inflammatory response early after Salmonella Typhimurium infection that was associated with low pathologic scores and low IFN-g production. This resulted in an increased interaction of Salmonella with the cecal epithelium and earlier systemic dissemination of the bacteria. The global transcriptional signature in the cecum of mouse during Salmonella infection showed normal expression of tissue specific genes and upregulation of type I IFN pathway in mutant mice. In control mice, there was a significant over-representation of genes involved in cellular recruitment and antibacterial activity paralleling the histopathological features. These results show the impact of USP18 in the development of Salmonella-induced typhlitis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

et al. 2011

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“…Even an increase in the copy number of the TLR4 gene in an individual does not confer it too much advantage in its mode of action indicating a fine balance in gene dosage and action acquired over time. In a recent study, Roy et al [35] investigated the response pattern of mice carrying one, two, or three copies of the TLR4 gene to Salmonella typhimurium infection and, although found a small difference in survival and bacterial load clearance in individuals carrying three copies of the gene, opined that two copies of the gene per individual represents the most optimal dose possible to fight infections.…”

Section: Discussionmentioning

confidence: 99%

Bacterial lipopolysaccharide induces increased expression of toll-like receptor (TLR) 4 and downstream TLR signaling molecules in bovine mammary epithelial cells

et al. 2007

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-Bovine mammary epithelial cells contribute to the innate immune response to intramammary infections by recognizing pathogens through specialized pattern recognition receptors. Toll-like receptor 4 (TLR4) is one such receptor that binds and is activated by lipopolysaccharide (LPS), a component of the outer envelope of Gram-negative bacteria. In this study, MAC-T cells (a bovine mammary epithelial cell line) were incubated in the presence or absence of increasing concentrations of LPS for 24 h. Expression of TLR2 and TLR4 were analyzed at both mRNA and protein levels by quantitative real-time PCR (qPCR) and flow cytometry, respectively. The mRNA of both receptors were up-regulated by all concentrations of LPS used (P < 0.01). Similarly, flow cytometry with specific antibodies against TLR2 and TLR4 detected increased surface expression of these proteins. Furthermore, expression of downstream TLR4 signaling molecules was examined by qPCR following varying exposure times to 1 μg/mL of LPS. Results demonstrate that the required adaptor molecules and transcription factors were up-regulated in a time-dependent manner. Both the MyD88 dependent and independent pathways in TLR4 signaling were activated in MAC-T cells. Expression of TOLLIP increased in response to LPS as did the pro-apoptotic protease, CASP8. These results suggest that the bovine mammary epithelium possesses the necessary immune repertoires required to achieve a robust defense against E. coli. The current findings, coupled with previous findings that S. aureus ligands induce up-regulation of TLR4, may indicate a positive adaptation by mammary epithelial cells to effectively respond to different types of mastitis pathogens.lipopolysaccharide / TLR4 and TLR2 / signal transduction / bovine mammary epithelial cells / mastitis

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“…between mouse and human (12). In support for this hypothesis, a number of recent studies used Tlr4 transgenic mice to demonstrate that Tlr4 expression levels (depending on the transgene dosage) determine the extent of innate responses to LPS (13)(14)(15).…”

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confidence: 98%

Transcription Factor PU.1 Controls Transcription Start Site Positioning and Alternative TLR4 Promoter Usage

Lichtinger

Ingram

Hornef

et al. 2007

Journal of Biological Chemistry

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Human and mouse show markedly different sensitivities toward bacterial endotoxins, and recent evidence suggests that a species-specific regulation of the lipopolysaccharide receptor Toll-like receptor 4 (Tlr4) may contribute to this phenomenon. To gain further insight into mechanisms of Tlr4 regulation, we conducted a detailed in vivo and in vitro study of the murine Tlr4 gene, including analysis of transcription start site location, transcription factor occupancy, and activities of its proximal regulatory sequences. Our analyses identified a PU.1-dependent myeloid promoter, which is conserved between humans and mouse. We also identified an additional, distal promoter, located ϳ200 bp upstream of the myeloid-specific promoter, which is a functional target of E-box binding factors. In contrast to humans, where non-myeloid cells utilize both promoters, the distal Tlr4 promoter initiates all Tlr4 transcripts in murine non-myeloid cells, indicating that species-specific differences in TLR4 mRNA regulation may primarily exist in non-myeloid cell types. Interestingly, PU.1 null murine myeloid progenitor cells predominantly use the distal promoter, and the conditional induction of PU.1 expression in these cells leads to the rapid switch of transcription initiation to the proximal myeloid promoter. This indicates a direct role for PU.1 in determining the transcriptional start site and in recruiting the basal transcription machinery to myeloid promoters.Cell type-specific gene regulation in mononuclear phagocytes is controlled by a number of specific transcription factors including members of the ETS, CCAAT/enhancer-binding protein, and Core binding factor families (1-3). A large number of macrophage-specific promoters share common sequence properties; 5Ј-regulatory regions are often TATA-less and GCpoor and often lack classical initiator (INR) 3 sequences.

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Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes

Cited by 34 publications

References 44 publications

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

Bacterial lipopolysaccharide induces increased expression of toll-like receptor (TLR) 4 and downstream TLR signaling molecules in bovine mammary epithelial cells

Transcription Factor PU.1 Controls Transcription Start Site Positioning and Alternative TLR4 Promoter Usage

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