The pathological mechanisms of Dengue are still unknown and it has not been possible to produce any treatment or vaccine. The only current prevention method is vector control.
This context brought IRD immunology and virology specialists and their research partners (1) to focus on these little-known biological mechanisms that are set into operation on infection by the virus, responsible for increasing the permeability of vascular wall endothelial cells and hence blood loss. The researchers found evidence of the role played by particular enzymes, metalloproteinases, in the occurrence of this leakage.
Low concentrations of these enzymes are present naturally in the organism, and they are involved in the reconfiguration of organ tissues during human embryonic development or tissue repair, but also in the development of certain cancers. They attack specifically the intercellular cement that binds the vascular walls. The research team demonstrated, in vitro, that Dengue-virus infection of certain targeted cells of the immune system (the dendritic cells) triggered an inflammatory reaction, stimulating these same target cells to overproduce metalloproteinases (gelatinolytic matrix metalloproteinases – MMP-9) and secrete them into the cellular supernatant (2). The quantity of enzyme produced therefore appears to be proportional to the concentration of viral particles present.
To verify that the metalloproteinases were the only agents responsible for the increased vascular permeability, the researchers performed tests on cell cultures of endothelial tissue, of the same type as that of the blood vessel walls. The supernatant of the infected cells, consequently containing the metalloproteinases, were brought into contact with this tissue. The vascular permeability, estimated by the quantity of supernatant passing through the endothelial tissue, appeared significantly higher. Conversely, the natural permeability of the tissue was restored when a specific inhibitor of these enzymes (SB-3CT) was added to the supernatant. Fluorescence microscope images of proteins of the intercellular cement, subjected to the action of the same supernatant, revealed that metalloproteinases act on the blood vessel walls like biological “scissors”: they destroy the protein bonds which maintain cell adhesion and hence keep them together. This action was, however, neutralized by specific metalloproteinase inhibitors.
A series of in vivo experiments following the same principle confirmed these hypotheses. A mouse model with blood circulatory system coloured blue was injected with supernatant containing these enzymes, on their own or in the presence of their inhibitor. This procedure not only reproduced the mechanisms of vascular rupture that originated blood leakage, but also – and more significantly – succeeded in neutralizing them.
This research sheds completely new light on Dengue’s pathological strategy. The results provide a way of explaining the major role played by direct action of metalloproteinases on blood-vessel walls. The overproduction of these enzymes, linked to the viral infection and the inflammatory reaction it triggers, does not however appear to be restricted to Dengue. The mechanism described here could provide a molecular basis for a new model of the action of other known haemorrhage-inducing viruses, such as Ebola, Marburg, or Hanta. New lines of therapeutic research against these pathologies, for which no treatment yet exists, can now be envisaged. Indeed, clinical trials on Dengue are currently in preparation.
(2)The cell supernatant corresponds to the culture medium of the infected cells.
Marie Guillaume | alfa
Antimicrobial substances identified in Komodo dragon blood
23.02.2017 | American Chemical Society
New Mechanisms of Gene Inactivation may prevent Aging and Cancer
23.02.2017 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
23.02.2017 | Physics and Astronomy
23.02.2017 | Earth Sciences
23.02.2017 | Life Sciences