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Ghent University discovers how EBV inactivates immunesystem

Discussion in 'Other Health News and Research' started by Spring, Aug 20, 2012.

  1. Spring

    Spring Senior Member

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    See: http://www.alphagalileo.org/ViewItem.aspx?ItemId=123271&CultureCode=en

    Cannot copy the text of the article.

    It says they found EBV can inactivate a cytokine, human CSF-1, which is essential for innate and adaptive Immunity against viral and microbial infections, and cancer.

    They used 3d images to atomic resolution of how BARF1 captures and inactivates Human CSF-1, and to unravel moleculair mechanism of this inactivation.

    (Found on MEnet)
     
  2. Overstressed

    Overstressed Senior Member

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    Belgium
  3. lansbergen

    lansbergen Senior Member

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    http://en.wikipedia.org/wiki/Colony-stimulating_factor

    Etymology

    The name "colony-stimulating factors" comes from the method by which they were discovered.

    Hemopoietic stem cells were cultured (see cell culture) on a so-called semisolid matrix, which prevents cells from moving around, so that, if a single cell starts proliferating, all of the cells derived from it will remain clustered around the spot in the matrix where the first cell was originally located. These are referred to as "colonies." Therefore, it was possible to add various substances to cultures of hemopoietic stem cells and then examine which kinds of colonies (if any) were "stimulated" by them.

    The substance that was found to stimulate formation of colonies of macrophages, for instance, was called macrophage colony-stimulating factor, for granulocytes, granulocyte colony-stimulating factor, and so on.


    Colony-stimulating factors include:

    CSF1 - macrophage colony-stimulating factor [​IMG]
     
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  4. Spring

    Spring Senior Member

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    I wonder how -and if- nagalase and natural GcMaf (I mean one's own, not injected GcMaf) are related in some way or if it is a completely different mechanism. Looks like it is different. But both mechanisms seem to inactivate macrophages.
    Guess you can have them both which doesn't sound good.

    I hope KDM is in contact with this Belguim people.
     
  5. lansbergen

    lansbergen Senior Member

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    Macrophage colony-stimulating factor does not inactivate macrophages,

    The EBV protein inactivates CSF. .


     
  6. Firestormm

    Firestormm Guest

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    nature structural & molecular biology

    Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1

    Abstract: published 19 August 2012: http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2367.html

    Jonathan Elegheert, Nathalie Bracke, Philippe Pouliot, Irina Gutsche, Alexander V Shkumatov, Nicolas Tarbouriech, Kenneth Verstraete, Anaïs Bekaert, Wim P Burmeister, Dmitri I Svergun, Bart N Lambrecht, Bjorn Vergauwen & Savvas N Savvides

    Hematopoietic human colony-stimulating factor 1 (hCSF-1) is essential for innate and adaptive immunity against viral and microbial infections and cancer.

    The human pathogen Epstein-Barr virus secretes the lytic-cycle protein BARF1 that neutralizes hCSF-1 to achieve immunomodulation.

    Here we show that BARF1 binds the dimer interface of hCSF-1 with picomolar affinity, away from the cognate receptor–binding site, to establish a long-lived complex featuring three hCSF-1 at the periphery of the BARF1 toroid.

    BARF1 locks dimeric hCSF-1 into an inactive conformation, rendering it unable to signal via its cognate receptor on human monocytes.

    This reveals a new functional role for hCSF-1 cooperativity in signaling.

    We propose a new viral strategy paradigm featuring an allosteric decoy receptor of the competitive type, which couples efficient sequestration and inactivation of the host growth factor to abrogate cooperative assembly of the cognate signaling complex.
     
  7. Spring

    Spring Senior Member

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    lansbergen (sorry I cant quote on my device)

    Okay, CSF don't inactivate macrophages directly, but if CSF is inactivated macrophages aren't activated while they should. And nagalase prohibits GcMaf to activate macrophages when they should be activated. So both downregulate immune response by macrophages.
     
  8. Firestormm

    Firestormm Guest

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    It's at times like this that you appreciate articles, isn't it? And help with interpreting what is written. It's all Greek to me! :)
     
  9. Firestormm

    Firestormm Guest

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    Thanks Spring. I've copied it out below :)

    Ghent University scientists discover the mechanism of inactivation of a human cytokine important for immunity by the Epstein-Barr Virus

    20 August 2012 Ghent University

    http://www.alphagalileo.org/ViewItem.aspx?ItemId=123271&CultureCode=en

    Viruses co-evolved with their mammalian hosts by developing sophisticated interactions with host molecular targets that primarily serve to evade detection and elimination by the immune system.

    This is well reflected in strategies based on the secretion of viral protreins aiming to neutralize the activity of host cytokines and chemokines that are produced to mobilize immune system cells to areas of infection and to orchestrate an appropriate immune response.

    Understanding the molecular repertoire and strategies employed by global viral pathogens is especially important at a time when large-scale studies continue to uncover the genetic and proteomic diversity of viruses.

    The Epstein-Barr Virus (EBV) is truly a global human pathogen that establishes life-long persistent infections in 90-95% of the human population, highlighting the fact that EBV must employ a very effective strategy in order to subvert detection and elimination by the human immune system.

    EBV is the causative agent for infectious mononucleosis (KLIERKOORTS), several lymphatic malignancies (e.g. Burkitt’s and Hodgkin’s lymphomas), and gastric and nasopharyngeal carcinomas (NPC).

    A striking aspect of the EBV proteomic pool concerns the secretion the protein BARF1, which in recent years was shown to be highly associated with epithelial malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinomas.

    The discovery that BARF1 is a binding protein for the essential hematopoietic cytokine hCSF-1 and that it can block monocyte proliferation established a link to the possible immunomodulatory role of BARF1.

    This is because the target for BARF1, the human cytokine CSF-1, is essential for innate and adaptive immunity against viral and microbial infections, and cancer.

    However, the structural and molecular basis of how BARF1 sequesters and inactivates CSF-1 had remained unknown for nearly two decades.

    By employing an interidisciplinary approach combining structural biology, biophysics, biochemistry, molecular and cellular biology, we succeeded in obtaining 3D images to atomic resolution of how BARF1 captures and inactivates human CSF-1, and to unravel the molecular mechanism of this inactivation.

    The most far-reaching dimension of our work is the uncovering of a unique mechanism for the inactivation of a human growth factor by a viral decoy receptor to achieve immunomodulation. BARF1 is structurally different from the cognate receptor for hCSF-1 and evolved to target a novel binding epitope at the dimer interface of hCSF-1 distinct from the cognate receptor binding site.

    Our discovery adds an important piece to the puzzle of how creatively viruses can evade the human immune system and offers opportunities to exploit such insights for therapeutic purposes.

    Importantly, we are reminded that the future may hold many such surprises regarding viral strategies to subvert the human immune system.

    In other words, we may have only scratched the tip of the iceberg!
     
  10. Spring

    Spring Senior Member

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    Thanks Firestorm for copying. It's better to have the article in the thread!
     
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  11. Firestormm

    Firestormm Guest

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    No worries. Just to add, because I didn't really say it above, but I am grateful to those who have tried to explain this one to a pleb like wot I is :)
     

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