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
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
19.10.2017 | Materials Sciences
19.10.2017 | Materials Sciences
19.10.2017 | Physics and Astronomy