Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Dengue and other haemorrhagic fevers: towards a first potential treatment

22.12.2006
Globally, 60 to 100 million people are hit by Dengue, a viral disease transmitted by mosquitoes of the genus Aedes. The most severe form of this disease, which causes blood loss, can lead to a fatal shock-like state (Dengue Shock Syndrome) with or without associated haemorrhage, and is currently increasing in tropical countries.

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.

Marie Guillaume-Signoret – IRD
Translation : Nicholas Flay
(1)These IRD investigations were conducted in partnership with research scientists from Mahidol University of Bangkok (Thailand), the company ImmunoClin Ltd (United Kingdom), research unit UMR 5535 CNRS/UM2 and unit 454 of INSERM (France).

(2)The cell supernatant corresponds to the culture medium of the infected cells.

Marie Guillaume | alfa
Further information:
http://www.ird.fr/fr/actualites/fiches/2006/fas254.pdf

Further reports about: Dengue metalloproteinase permeability supernatant vascular

More articles from Life Sciences:

nachricht Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>