In hot pursuit to defeat the enemy within
They are humankind’s greatest killer and rank among the hardest to treat of all diseases, claiming twice as many lives as cancer. But a discovery could give doctors a new weapon in the battle against viruses, including those that cause widespread illnesses such as the common cold and gastroenteritis.
In a report that has just been published, scientists revealed a previously unknown way that the immune system attacks infections, a finding that offers a new approach to treating diseases caused by viruses.
“Doctors have plenty of antibiotics to fight bacterial infections but few antiviral drugs. Although these are early days and we don’t yet know whether all viruses are cleared by this mechanism, we are excited that our discoveries may open multiple avenues for developing new antiviral drugs,” said Dr Leo James at the Laboratory for Molecular Biology in Cambridge, who led the study.
The body tackles infections by unleashing biological foot soldiers called antibodies that stick to viruses as they circulate in the bloodstream.
For the past 100 years, scientists working on immunity generally believed this made it harder for viruses to get inside healthy cells and so spread illness around the body. But the new study has shown that for many viruses, antibodies work in a very different way.
Instead of preventing viruses from infecting cells, the antibodies follow the invader inside and coordinate an immune attack from within.
Until now, the belief among immunologists was that antibodies went to work only outside cells. Once a virus had invaded a cell, it was thought to be too late for the immune system to do anything.
A virus is a microscopic bundle of genetic material that is wrapped in a protective protein coat. Viruses cannot multiply by themselves, but instead must hijack cells and replicate inside them. Scientists have identified millions of different viruses that infect humans, animals, plants and even bacteria.
In humans viruses are responsible for influenza, the common cold, smallpox, chickenpox, shingles, herpes, polio, rabies, Ebola, hanta fever, Aids and various forms of cancer.
In a series of experiments James’s group found that in many cases antibodies do very little to stop viruses from infecting cells. Instead, the antibodies cling to the viruses when they invade cells and use the cells’ own biological machinery to kill the virus.
James showed that, once inside an infected cell, antibodies attract a protein called TRIM21. This in turn signals to the cell’s equivalent of a waste disposal machine, a large cluster of proteins called a proteasome. When the proteasome arrives, it latches on to TRIM21 and goes to work, dismantling the virus piece by piece. The process happens quickly and often before the virus has a chance to cause harm.
The discovery, which is reported in the journal Proceedings of the National Academy of Sciences, could pave the way for a new generation of antiviral drugs that fight infections by supercharging the body’s own defences.
Future treatments based on James’s work are only expected to work against a class of viruses that do not shed their protein coats when they invade healthy cells. Those that do would leave the attached antibodies outside the cells and so not trigger the cell’s own immune attack.
James’s team has already begun investigating how to turn the finding into new drugs. Tests on cells in the laboratory show that administering TRIM21 boosts resistance to infection, presumably by bolstering the natural immune attack.
“Potentially, you could give TRIM21 to someone and it will work with all of the natural antibodies they are making,” James said. “When we look at infected cells at different time points, we can see that the virus is disappearing. And if we take out the TRIM21, that no longer happens.”
Writing in the journal, James explains that familiar viruses, such as those that cause the common cold, gastroenteritis and the winter vomiting bug, are all fought inside cells with help from antibodies.
Sir Greg Winter, the deputy director of the British Medical Research Council’s 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.”
If further studies confirm that infections can be effectively blocked by TRIM21, the researchers hope to move into animal and ultimately human trials.
Three familiar invaders that beat our defences:
The common cold
Caused by the human rhinovirus and named after the Greek for nose, it affects more people than any other virus. There are around 200 different viruses that cause the cold and it is this variability, combined with its ability to mutate, that makes the common cold so hard to cure. Adults can expect to catch two to four colds a year. Children, who have less-developed immune systems, typically get three to eight colds a year.
This is the leading cause of severe diarrhoea and dehydration in children in developed and developing countries and is caused by the rotavirus, which infects the stomach and bowel. The World Health Organisation estimates that the rotavirus is to blame for between 20% and 70% of hospital admissions due to diarrhoea.
Winter vomiting disease
Caused by norovirus, or “small round structured virus”, it is highly infectious and spreads quickly through hospitals, schools, nursing homes and on cruise ships—where people are in closely confined environments. The illness is generally mild but can take people two or three days to get over. Unlike rotavirus, people are susceptible to norovirus at any age, because immunity to the bug is short-lived.—