How immune protein differentiates between own RNA and virus RNA

10 August 2014

Reovirus infection. Coloured transmission electron micrograph (TEM) of a section through a cell infected with reovirus particles (red).

Image: Reovirus infection. Coloured transmission electron micrograph (TEM) of a section through a cell infected with reovirus particles (red).©  EYE OF SCIENCE/SCIENCE PHOTO LIBRARY

Researchers at Cancer Research UK's London Research Institute (LRI; now part of the Francis Crick Institute) have answered a long-standing question about how a protein that plays a key role in our immune systems recognises different families of viruses - including influenza and rotavirus.  

It's hoped that the work will lead to the design of new drugs that could trigger immunity to viruses or even cancer.

Dr Caetano Reis e Sousa of LRI explained: "Researchers at the Medical Research Council's National Institute for Medical Research discovered in the 1950s that all cells react to viral invasion by sending an alert signal to themselves and uninfected neighbours via proteins called type I interferons. The cells receiving the interferon signal then put up antiviral defences to block infection.

"The key question is how a cell can tell that it is infected and start making interferons."

In 2006 Dr Reis e Sousa and his team showed that this would happen if a cell detected a certain signature on a piece of RNA - three phosphate molecules, called a tri-phosphate - at a particular end of a molecule of RNA. This signature is found on many RNA viruses, including the flu virus, but is not usually found in uninfected human cells.

The protein that detects the triphosphate on the RNA is called RIG-I. Unexpectedly, the team discovered that RIG-I also mediates immunity to other viruses that don't have a triphosphate group, including reoviruses - the family that includes the human pathogen rotavirus.

To investigate how RIG-I recognises these other viruses, Dr Reis e Sousa and his colleagues studied interferon responses in cells grown in the laboratory and in mice with and without RIG-I present.

They discovered that, although members of the reovirus family don't have three phosphates at the end of their RNA, they do have two - and RIG-I can bind to these diphosphates in the same way. The research provides a unifying explanation for how RIG-I can provoke immunity against different families of RNA viruses.

Dr Reis e Sousa said: "RIG-I, a single innate immune receptor, can discriminate between self and virus RNA by recognising virus RNA molecules that possess either a di- or a triphosphate, while ignoring self RNA that has been processed to leave either no free phosphate or a single phosphate.

"This is a simple and elegant means of self/non-self discrimination and can be used to design new molecules that may be useful in triggering immunity to cancer or some viruses."

The paper, Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates, is published in Nature.

  • The answer to a long-standing quandary about how an important immune protein recognises separate families of RNA viruses with different signatures is hoped to lead to the design of new drugs to trigger immunity against such viruses - and even against cancer. 
  • RNA is a family of molecules with many different genetic roles. For instance, the genes on human DNA are copied into a type of RNA before being translated into the proteins that our cells need to carry out their functions. Like DNA, RNA can carry its own genetic information - and in fact, many virus families have genomes composed of RNA. 
  • The work was carried out by a team at Cancer Research UK's London Research Institute who worked with colleagues from University Hospital Bonn in Germany and the Vanderbilt School of Medicine in Tennessee, USA.