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

2002 ◽  
Vol 196 (8) ◽  
pp. 1017-1024 ◽  
Author(s):  
Andreas Sing ◽  
Dagmar Rost ◽  
Natalia Tvardovskaia ◽  
Andreas Roggenkamp ◽  
Agnès Wiedemann ◽  
...  
Keyword(s):  
Immune Response ◽  
Defense Mechanisms ◽  
Cell Activation ◽  
Yersinia Pseudotuberculosis ◽  
Interleukin 10 ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2 ◽  
V Antigen ◽  
Enteropathogenic Yersinia ◽  
The Impact

A characteristic of the three human-pathogenic Yersinia spp. (the plague agent Yersinia pestis and the enteropathogenic Yersinia pseudotuberculosis and Yersinia enterocolitica) is the expression of the virulence (V)-antigen (LcrV). LcrV is a released protein which is involved in contact-induced secretion of yersinia antihost proteins and in evasion of the host's innate immune response. Here we report that recombinant LcrV signals in a CD14- and toll-like receptor 2 (TLR2)-dependent fashion leading to immunosuppression by interleukin 10 induction. The impact of this immunosuppressive effect for yersinia pathogenesis is underlined by the observation that TLR2-deficient mice are less susceptible to oral Y. enterocolitica infection than isogenic wild-type animals. In summary, these data demonstrate a new ligand specificity of TLR2, as LcrV is the first known secreted and nonlipidated virulence-associated protein of a Gram-negative bacterium using TLR2 for cell activation. We conclude that yersiniae might exploit host innate pattern recognition molecules and defense mechanisms to evade the host immune response.

scholarly journals Growth of Yersinia pseudotuberculosis in Mice Occurs Independently of Toll-Like Receptor 2 Expression and Induction of Interleukin-10

2007 ◽  
Vol 75 (7) ◽  
pp. 3561-3570 ◽  
Author(s):  
Victoria Auerbuch ◽  
Ralph R. Isberg
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokine ◽  
Yersinia Pseudotuberculosis ◽  
Interleukin 10 ◽  
Cytokine Response ◽  
Target Cells ◽  
Toll Like Receptor ◽  
Mouse Tissues ◽  
Tnf Α ◽  
Toll Like Receptor 2

ABSTRACT Pathogenic Yersinia translocates effector proteins into target cells via a type III secretion system (TTSS), modulating the host immune response. A component of the TTSS translocon, LcrV, has been implicated in preventing inflammation through Toll-like receptor 2 (TLR2) by inducing expression of the anti-inflammatory cytokine interleukin-10 (IL-10). TLR2−/− mice were reported to be less susceptible to the enteropathogen Yersinia enterocolitica. To determine whether TLR2 also plays a role in recognition of the enteropathogen Yersinia pseudotuberculosis and whether this results in an immune response that is detrimental to the host, we evaluated the macrophage cytokine response to live Y. pseudotuberculosis and analyzed the susceptibility of TLR2−/− mice to enteropathogenic Yersinia. We find that Yersinia induction of macrophage IL-10 occurs independently of TLR2 and LcrV and is blocked by the TTSS. In particular, the TTSS effector protein YopJ, which inhibits production of the inflammatory cytokine tumor necrosis factor alpha (TNF-α), also inhibits IL-10 expression. Consistent with these results, IL-10 is undetectable in Y. pseudotuberculosis-infected mouse tissues until advanced stages of infection. In addition, we find that TLR2−/− mice (derived independently from those used in previous studies) do not display altered susceptibility to enteropathogenic Yersinia compared to wild-type mice. Tissue levels of IL-10, as well as the inflammatory cytokines TNF-α, IL-6, and gamma interferon and the chemokine macrophage chemotactic protein 1, are similar in TLR2+/+ and TLR2−/− mice during enteropathogenic Yersinia infection. Therefore, the absence of TLR2 alone does not affect the cytokine response of macrophages to, or the in vivo growth and survival of, enteropathogenic Yersinia.

scholarly journals Interactions between Yersinia pestis V-antigen (LcrV) and human Toll-like receptor 2 (TLR2) in a modelled protein complex and potential mechanistic insights

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Tiandi Wei ◽  
Jing Gong ◽  
Guojing Qu ◽  
Mingyu Wang ◽  
Hai Xu
Keyword(s):  
Immune Response ◽  
Yersinia Pestis ◽  
Mechanistic Model ◽  
White Blood Cells ◽  
Dynamics Simulation ◽  
Structure Model ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2 ◽  
V Antigen

Abstract Background Yersinia pestis, the etiological pathogen of plague, is capable of repressing the immune response of white blood cells to evade phagocytosis. The V-antigen (LcrV) was found to be involved in this process by binding to human Toll-like Receptor 2 (TLR2). The detailed mechanism behind this LcrV and TLR2 mediated immune response repression, however, is yet to be fully elucidated due to the lack of structural information. Results In this work, with protein structure modelling, we were able to construct a structure model of the heterotetramer of Y. pestis LcrV and human TLR2. Molecular dynamics simulation suggests the stability of this structure in aquatic environment. The LcrV model has a dumbbell-like structure with two globule domains (G1 at N-terminus and G2 away from membrane) connected with a coiled-coil linker (CCL) domain. The two horseshoe-shape TLR2 subunits form a V-shape structure, are not in direct contact with each other, and are held together by the LcrV homodimer. In this structure model, both the G1 and CCL domains are involved in the formation of LcrV homodimer, while all three domains are involved in LcrV-TLR2 binding. A mechanistic model was proposed based on this heterotetrameric structure model: The LcrV homodimer separates the TLR2 subunits to inhibit the dimerization of TLR2 and subsequent signal transfer for immune response; while LcrV could also inhibit the formation of heterodimers of TLR2 with other TLRs, and leads to immune response repression. Conclusions A heterotetrameric structure of Y. pestis LcrV and human TLR2 was modelled in this work. Analysis of this modelled structure showed its stability in aquatic environments and the role of LcrV domains and residues in protein-protein interaction. A mechanistic model for the role of LcrV in Y. pestis pathogenesis is raised based on this heterotetrameric structure model. This work provides a hypothesis of LcrV function, with which further experimental validation may elucidate the role of LcrV in human immune response repression.

scholarly journals Regiospecific Methylation of a Dietary Flavonoid Scaffold Selectively Enhances IL-1β Production following Toll-like Receptor 2 Stimulation in THP-1 Monocytes

2013 ◽  
Vol 288 (29) ◽  
pp. 21126-21135 ◽  
Author(s):  
Eng-Kiat Lim ◽  
Paul J. Mitchell ◽  
Najmeeyah Brown ◽  
Rebecca A. Drummond ◽  
Gordon D. Brown ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Natural Products ◽  
Intestinal Microflora ◽  
Rank Order ◽  
Inflammasome Activation ◽  
Toll Like Receptor ◽  
Immune Health ◽  
Toll Like Receptor 2 ◽  
Dietary Flavonoid ◽  
The Impact

It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4′-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.

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