Salp15 Binding to DC-SIGN Inhibits Cytokine Expression

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Yvonne
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Salp15 Binding to DC-SIGN Inhibits Cytokine Expression

Post by Yvonne » Sun 24 Feb 2008 11:33

PLoS Pathog. 2008 Feb 15;4(2):e31 [Epub ahead of print] Links

Salp15 Binding to DC-SIGN Inhibits Cytokine Expression by Impairing both Nucleosome Remodeling and mRNA Stabilization.

Hovius JW, de Jong MA, den Dunnen J, Litjens M, Fikrig E, van der Poll T, Gringhuis SI, Geijtenbeek TB.

Ixodes ticks are major vectors for human pathogens, such as Borrelia burgdorferi, the causative agent of Lyme disease. Tick saliva contains immunosuppressive molecules that facilitate tick feeding and B. burgdorferi infection. We here demonstrate, to our knowledge for the first time, that the Ixodes scapularis salivary protein Salp15 inhibits adaptive immune responses by suppressing human dendritic cell (DC) functions. Salp15 inhibits both Toll-like receptor- and B. burgdorferi-induced production of pro-inflammatory cytokines by DCs and DC-induced T cell activation. Salp15 interacts with DC-SIGN on DCs, which results in activation of the serine/threonine kinase Raf-1. Strikingly, Raf-1 activation by Salp15 leads to mitogen-activated protein kinase kinase (MEK)-dependent decrease of IL-6 and TNF-alpha mRNA stability and impaired nucleosome remodeling at the IL-12p35 promoter. These data demonstrate that Salp15 binding to DC-SIGN triggers a novel Raf-1/MEK-dependent signaling pathway acting at both cytokine transcriptional and post-transcriptional level to modulate Toll-like receptor-induced DC activation, which might be instrumental to tick feeding and B. burgdorferi infection, and an important factor in the pathogenesis of Lyme disease. Insight into the molecular mechanism of immunosuppression by tick salivary proteins might provide innovative strategies to combat Lyme disease and could lead to the development of novel anti-inflammatory or immunosuppressive agents.

PMID: 18282094

Introduction
Ixodes ticks are a major arthropod vector for human pathogens, such as Borrelia burgdorferi, the causative agent of Lyme disease [1]. Ixodes ticks require five to seven days to feed to repletion [2]. In order to secure attachment of the vector and to ensure susceptibility of reservoir hosts for future tick infestations, tick saliva contains modulators of host immune responses. Salp15, a 15-kDa salivary gland protein, is a major immunomodulatory protein in I. scapularis saliva [3]. Salp15 has been shown to bind to CD4, thereby inhibiting T cell receptor (TCR) ligation-induced signals, resulting in impaired interleukin (IL)-2 production and impaired CD4+ T cell activation and proliferation [4–6]. While feeding on a host, ticks can introduce B. burgdorferi into the host's skin. Local immunosuppression of the host by tick molecules assists B. burgdorferi in establishing an infection. In addition, it has been shown that Salp15 binds to B. burgdorferi outer surface protein (Osp) C [7]. B. burgdorferi expresses OspC in the tick salivary glands and during the early stages of mammalian infection. Binding of Salp15 to OspC protects the spirochete from antibody-mediated killing by the immune host [7], and silencing of Salp15 by RNA interference in I. scapularis ticks resulted in a dramatically impaired ability to transmit B. burgdorferi to an immune host [7]. Thus, Salp15 is an important immunomodulatory protein in I. scapularis saliva that targets the T cell arm of adaptive immunity.

Dendritic cells (DCs) are essential in initiating adaptive immune responses in naive hosts [8]. After sensing invading pathogens in peripheral tissues, DCs capture them for processing and presentation to activate T cells in draining lymph nodes [8]. Previously we have shown that Salp15 is secreted by the feeding tick and is locally introduced in the host skin [4], where Salp15 also provides B. burgdorferi a survival advantage in a naive murine host, but only when co-injected, ruling out a systemic immunosuppressive effect of Salp15 [7]. However, local inhibition of immune responses by Salp15 could be responsible for the observed effect. Under normal circumstances there are very few T lymphocytes present at the site of the tick-bite, whereas DCs are abundantly present. Therefore, we hypothesized that DCs are a major target for immunomodulation by Salp15, since these cells are essential in initiating adaptive immune responses to exposed tick (salivary gland) antigens and B. burgdorferi in a naive host.

Here we have investigated the interaction of the major immunomodulatory protein in Ixodes scapularis saliva, Salp15, with human DCs. Salp15 inhibits the production of the pro-inflammatory cytokines IL-12p70, IL-6, and TNF-α of DCs stimulated with the Toll-like receptor (TLR)-2 and −4 ligands, LTA and LPS, respectively. Salp15 interacts with the C-type lectin DC-SIGN, which results in activation of the kinases Raf-1 and mitogen-activated protein kinase kinase (MEK). This leads to the inhibition of pro-inflammatory cytokine production and suppresses the T cell–stimulatory role of DCs. Strikingly, the Salp15/DC-SIGN-induced signaling pathway regulates the inhibition of pro-inflammatory cytokines at different levels: decreased nucleosome remodeling at the IL-12p35 promoter impairs IL-12p70 production, whereas the inhibition of IL-6 and TNF-α is caused by an increased decay of their respective mRNAs. A similar suppression of pro-inflammatory cytokines is observed when DCs are activated with viable B. burgdorferi in the presence of Salp15, indicating that the spirochete uses Salp15 to induce immune suppression. Thus, local interaction of Salp15 and DCs will lead to immunosuppression, which potentially allows the tick to feed for a longer period of time, and B. burgdorferi to escape from human immune responses, and might therefore be an important factor in the pathogenesis of Lyme disease.

http://pathogens.plosjournals.org/perls ... 40031&ct=1
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minx
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Re: Salp15 Binding to DC-SIGN Inhibits Cytokine Expression

Post by minx » Sun 24 Feb 2008 13:24

Lovely research. But why didn't they use the Ixodus Ricinus, the main vector in Europe :o

minx
Posts: 96
Joined: Fri 27 Jul 2007 13:50

Re: Salp15 Binding to DC-SIGN Inhibits Cytokine Expression

Post by minx » Sun 24 Feb 2008 13:37

And to show nature is only fair; every disadvantage has it's advantage: (or: as the famous dutch soccerplayer Johan Cruijff once said: "elk nadeel heb s'n voordeel" :D )

http://www.lymeneteurope.org/forum/view ... ead#unread

Nick
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Re: Salp15 Binding to DC-SIGN Inhibits Cytokine Expression

Post by Nick » Sun 24 Feb 2008 22:57

I guess we now have to wait if the Steere/Wormser clan files a patent based on Salp15 to cure auto-immune diseases like chronic lyme :mrgreen:

minx
Posts: 96
Joined: Fri 27 Jul 2007 13:50

Re: Salp15 Binding to DC-SIGN Inhibits Cytokine Expression

Post by minx » Mon 25 Feb 2008 21:41

Nick wrote:I guess we now have to wait if the Steere/Wormser clan files a patent based on Salp15 to cure auto-immune diseases like chronic lyme :mrgreen:
Great, I think you just found a new alternative cure for chronic lyme disease. Instead of bee-sting therapy we prescribe tick-bite therapy :woohoo:

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