Yersinia V–Antigen Exploits Toll-like Receptor 2 and CD14 for Interleukin 10–mediated Immunosuppression

Sing, Andreas; Rost, D; Tvardovskaia, Natalia; Roggenkamp, Andreas; Wiedemann, Agnès; Kirschning, Carsten J.; Aepfelbacher, Martin; Heesemann, Jürgen

doi:10.1084/jem.20020908

Cited by 298 publications

(264 citation statements)

References 31 publications

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“…The finding that infection with YopJ + strains yields DC that are unresponsive to LPS (at least as measured by cytokine induction) indicates that YopJ is not simply generating immature but responsive DC, but a cell that is more functionally fixed. While an effect on TLR4-mediated responses by Yersinia virulence factors has not been reported, Yersinia V-antigen has been found to modulate TLR2 responses in macrophages to induce immunosuppressive IL-10 secretion [53]. Although it is possible that YopJ is mediating these effects through pathways other than NF-jB and MAPK, many of our current findings are consistent with the previous studies using pharmacological inhibitors or gene knockout.…”

Section: Discussionsupporting

confidence: 91%

Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis

et al. 2007

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Yersinia pestis evades immune responses in part by injecting into host immune cells several effector proteins called Yersinia outer proteins (Yops) that impair cellular function. This has been best characterized in the innate effector cells, but much less so for cells involved in adaptive immune responses. Dendritic cells (DC) sit at the crossroads between innate and adaptive immunity, and can function to initiate or inhibit adaptive immune responses. Although Y. pestis can target and inactivate DC, the mechanism responsible for this remains unclear. We have found that injection of Y. pestis YopJ into DC progenitors disrupts key signal transduction pathways and interferes with DC differentiation and subsequent function. YopJ injection prevents upregulation of the NF-jB transcription factor Rel B and inhibits MAPK/ERK activationboth having key roles in DC differentiation. Furthermore, YopJ injection prevents costimulatory ligand up-regulation, LPS-induced cytokine expression, and yields differentiated DC with diminished capability to induce T cell proliferation and IFN-c induction. By modulating DC function through YopJ-mediated disruption of signaling pathways during progenitor to DC differentiation, Yersinia may interfere with the adaptive responses necessary to clear the infection as well as establish a tolerant immune environment that leads to chronic infection/carrier state in the surviving host.

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Section: Discussionsupporting

confidence: 91%

Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis

et al. 2007

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“…Other secreted proteins behave in multiple ways. For example, the Yersinia effector LcrV is secreted by the type III secretion system and is required for the secretion of other type III effectors (24,25).…”

Section: Discussionmentioning

confidence: 99%

Mutually dependent secretion of proteins required for mycobacterial virulence

Fortune

Jaeger²,

Sarracino³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

355

410

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The ESX-1 locus is a region critical for full virulence in Mycobacterium tuberculosis, which encodes two secreted proteins as well as other genes involved in their secretion. The mechanism of secretion of the two proteins, ESAT-6 and CFP-10, and their function remain unknown. Using proteomic methods to search for additional proteins secreted by the ESX-1 locus, we discovered that a protein encoded by a chromosomally unlinked gene, espA, is also secreted by strains that contain the ESX-1 locus but not by strains with ESX-1 deletions. Mutations in individual ESX-1 genes, including those that encode ESAT-6 and CFP-10, were found to block EspA secretion. Surprisingly, mutants that lack espA reciprocally failed to secrete ESAT-6 and CFP-10 and were as attenuated as ESX-1 mutants in virulence assays. The results indicate that secretion of these proteins, which are each critical for virulence of pathogenic mycobacteria, is mutually dependent. The results further suggest that discerning the nature of the interaction and the structure of macromolecular complexes will provide insights into both an alternative mechanism of protein secretion and mycobacterial virulence.ESAT-6 protein ͉ Mycobacterium tuberculosis ͉ virulence factor I nteractions between bacterial pathogens and their hosts occur at the surface of cells. Many pathogenic bacteria secrete proteins involved in virulence (1). These proteins often interfere with normal host defenses and allow bacteria to survive and multiply. Strikingly, many of these virulence factors are secreted by nonclassical secretory systems that, in some cases, facilitate translocation of proteins across host cell membranes (2, 3).During the evolution of Mycobacterium bovis Bacille Calmette-Guérin (BCG), the attenuated bacillus widely used as vaccine against tuberculosis, a major deletion removed a set of nine ORFs (4). Similar deletions are found in Mycobacterium microti (5) and the Dassie bacillus (6), other relatively avirulent mycobacteria. The BCG deletion, known as RD1, includes two genes that encode the abundantly secreted proteins, ESAT-6 and CFP-10. The RD1 deletion encompasses most but not all of a larger, 15-gene region known as ESX-1 (7), which is hypothesized to encode an alternative secretory system (8, 9).The proteins encoded by the ESX-1 locus clearly play an important role in virulence. The secreted proteins encoded within the locus are potent T cell antigens (7, 10, 11). More significantly, Mycobacterium tuberculosis strains with RD1 deletions are far less virulent in mice than strains that are otherwise isogenic (12-14). They replicate poorly and cause less pathology in both immunocompetent and immunocompromised mice, although the latter ultimately succumb to infection. RD1-deleted strains of Mycobacterium marinum elicit only very modest macrophage aggregation and granuloma formation in zebrafish (15). Additional work suggests the RD1-encoded proteins may disrupt host cell membranes. In M. tuberculosis, these proteins may be required for lysis of infected cells (13) and c...

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“…The TNF-␣ levels in the supernatants were evaluated by a commercially available capture ELISA using goat anti-mouse TNF-␣ mAbs as recommended by the manufacturer (Ref. 27; R&D Systems, McKinley Place, MN).…”

Section: Measurement Of Macrophage Tnf-␣ Productionmentioning

confidence: 99%

A Dominant Role of Toll-Like Receptor 4 in the Signaling of Apoptosis in Bacteria-Faced Macrophages

Haase

Kirschning

Sing

et al. 2003

The Journal of Immunology

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121

129

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Conserved bacterial components potently activate host immune cells through transmembrane Toll-like receptors (TLRs), which trigger a protective immune response but also may signal apoptosis. In this study, we investigated the roles of TLR2 and TLR4 as inducers of apoptosis in Yersinia enterocolitica-infected macrophages. Yersiniae suppress activation of the antiapoptotic NF-κB signaling pathway in host cells by inhibiting inhibitory κB kinase-β. This leads to macrophage apoptosis under infection conditions. Experiments with mouse macrophages deficient for TLR2, TLR4, or both receptors showed that, although yersiniae could activate signaling through both TLR2 and TLR4, loss of TLR4 solely diminished Yersinia-induced apoptosis. This suggests implication of TLR4, but not of TLR2, as a proapoptotic signal transducer in Yersinia-conferred cell death. In the same manner, agonist-specific activation of TLR4 efficiently mediated macrophage apoptosis in the presence of the proteasome inhibitor MG-132, an effect that was less pronounced for activation through TLR2. Furthermore, the extended stimulation of overexpressed TLR4 elicited cellular death in epithelial cells. A dominant-negative mutant of Fas-associated death domain protein could suppress TLR4-mediated cell death, which indicates that TLR4 may signal apoptosis through a Fas-associated death domain protein-dependent pathway. Together, these data show that TLR4 could act as a potent inducer of apoptosis in macrophages that encounter a bacterial pathogen.

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Yersinia V–Antigen Exploits Toll-like Receptor 2 and CD14 for Interleukin 10–mediated Immunosuppression

Cited by 298 publications

References 31 publications

Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis

Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis

Mutually dependent secretion of proteins required for mycobacterial virulence

A Dominant Role of Toll-Like Receptor 4 in the Signaling of Apoptosis in Bacteria-Faced Macrophages

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