Tuesday, 2 November 2010
In a dramatic breakthrough that could affect millions of lives, scientists have been able to show for the first time that the body's immune defences can destroy the common cold virus after it has actually invaded the inner sanctum of a human cell, a feat that was believed until now to be impossible.
The discovery opens the door to the development of a new class of antiviral drugs that work by enhancing this natural virus-killing machinery of the cell. Scientists believe the first clinical trials of new drugs based on the findings could begin within two to five years.
The researchers said that many other viruses responsible for a range of diseases could also be targeted by the new approach. They include the norovirus, which causes winter vomiting, and rotavirus, which results in severe diarrhoea and kills thousands of children in developing countries.
Viruses are still mankind's biggest killers, responsible for twice as many deaths as cancer, essentially because they can get inside cells where they can hide away from the body's immune defences and the powerful antibiotic drugs that have proved invaluable against bacterial infections.
However, a study by a team of researchers from the world-famous Laboratory of Molecular Biology in Cambridge has shown that this textbook explanation of the limits of the human immune system is wrong because anti-viral antibodies can in fact enter the cell with the invading virus where they are able to trigger the rapid destruction of the foreign invader.
"In any immunology textbook you will read that once a virus makes it into a cell, that is game over because the cell is now infected. At that point there is nothing the immune response can do other than kill that cell," said Leo James, who led the research team.
But studies at the Medical Research Council's laboratory have found that the antibodies produced by the immune system, which recognise and attack invading viruses, actually ride piggyback into the inside of a cell with the invading virus.
Once inside the cell, the presence of the antibody is recognised by a naturally occurring protein in the cell called TRIM21 which in turn activates a powerful virus-crushing machinery that can eliminate the virus within two hours – long before it has the chance to hijack the cell to start making its own viral proteins. "This is the last opportunity a cell gets because after that it gets infected and there is nothing else the body can do but kill the cell," Dr James said.
"The antibody is attached to the virus and when the virus gets sucked inside the cell, the antibody stays attached, there is nothing in that process to make the antibody to fall off.
"The great thing about it is that there shouldn't be anything attached to antibodies in the cell, so that anything that is attached to the antibody is recognised as foreign and destroyed."
In the past, it was thought that the antibodies of the immune system worked entirely outside the cells, in the blood and other extra-cellular fluids of the body. Now scientists realise that there is another layer of defence inside the cells where it might be possible to enhance the natural anti-virus machinery of the body.
"The beauty of it is that for every infection event, for every time a virus enters a cell, it is also an opportunity for the antibody in the cells to take the virus out," Dr James said.
"That is the key concept that is different from how we think about immunity. At the moment we think of professional immune cells such as T-cells [white blood cells] that patrol the body and if they find anything they kill it.
"This system is more like an ambush because the virus has to go into the cell at some point and every time they do this, this immune mechanism has a chance of taking it out," he explained.
"It's certainly a very fast process. We've shown that once it enters the cell it gets degraded within an hour or two hours, that's very fast," he added.
The study, published in the journal Proceedings of the National Academy of Sciences, involved human cells cultured in the laboratory and will need to be replicated by further research on animals before the first clinical trials with humans.
One possibility is that the protein TRIM21 could be used in a nasal spray to combat the many types of viruses that cause the common cold. "The kind of viruses that are susceptible to this are the rhinoviruses, which cause the common cold, noravirus, which causes winter vomiting, rotavirus, which cause gastroenteritis. In this country these are the kind of viruses that people are most likely to be exposed to," Dr James said.
"This is a way of boosting all the antibodies you'd be naturally making against the virus. The advantage is that you can use that one drug against potentially lots of viral infections."
"We can think of administering these drugs as nasal sprays and inhalers rather than taking pills... It could lead to an effective treatment for the common cold," he said. "The beauty of this system is that you give the virus no chance to make its own proteins to fight back. It is a way for the cell to get rid of the virus and stay alive itself."
Sir Greg Winter, deputy director of the MRC Laboratory of Molecular Biology, said: "Antibodies are formidable molecular war machines; it now appears that they can continue to attack viruses within cells. This research is not only a leap in our understanding of how and where antibodies work, but more generally in our understanding of immunity and infection."
How the virus is tackled
[See 8 slides: http://is.gd/gD80s ]
* 1 Virus (purple) circulating in the bloodstream recognised by antibodies (yellow) of the immune system
* 2 Virus attaches to outer cell membrane with antibodies still attached
* 3 Virus invades the cell membrane and emerges inside the cell
* 4 Remains of cell membrane disappear and the virus is free to hijack the cell
* 5 TRIM21 protein (blue) recognises attached antibodies as foreign material
* 6 Powerful virus-destroying machines (cylinders) attracted to virus by TRIM21
* 7 Virus rapidly broken down and disabled within hours