Scientists discover viral 'Enigma machine'

Researchers have cracked a code that governs infections by a major group of viruses including the common cold and polio.

Until now, scientists had not noticed the code, which had been hidden in plain sight in the sequence of the ribonucleic acid (RNA) that makes up this type of viral genome.

But a paper published in the Proceedings of the National Academy of Sciences (PNAS) Early Edition by a group from the University of Leeds and University of York unlocks its meaning and demonstrates that jamming the code can disrupt virus assembly. Stopping a virus assembling can stop it functioning and therefore prevent disease.

Professor Peter Stockley, Professor of Biological Chemistry in the University of Leeds' Faculty of Biological Sciences, who led the study, said: "If you think of this as molecular warfare, these are the encrypted signals that allow a virus to deploy itself effectively."

"Now, for this whole class of viruses, we have found the 'Enigma machine'--the coding system that was hiding these signals from us. We have shown that not only can we read these messages but we can jam them and stop the virus' deployment."

Single-stranded RNA viruses are the simplest type of virus and were probably one of the earliest to evolve. However, they are still among the most potent and damaging of infectious pathogens.

Rhinovirus (which causes the common cold) accounts for more infections every year than all other infectious agents put together (about 1 billion cases), while emergent infections such as chikungunya and tick-borne encephalitis are from the same ancient family.

Other single-stranded RNA viruses include the hepatitis C virus, HIV and the winter vomiting bug norovirus.

This breakthrough was the result of three stages of research.

• In 2012, researchers at the University of Leeds published the first observations at a single-molecule level of how the core of a single-stranded RNA virus packs itself into its outer shell--a remarkable process because the core must first be correctly folded to fit into the protective viral protein coat. The viruses solve this fiendish problem in milliseconds. The next challenge for researchers was to find out how the viruses did this.

• University of York mathematicians Dr Eric Dykeman and Professor Reidun Twarock, working with the Leeds group, then devised mathematical algorithms to crack the code governing the process and built computer-based models of the coding system.

• In this latest study, the two groups have unlocked the code. The group used single-molecule fluorescence spectroscopy to watch the codes being used by the satellite tobacco necrosis virus, a single stranded RNA plant virus.

Dr Roman Tuma, Reader in Biophysics at the University of Leeds, said: "We have understood for decades that the RNA carries the genetic messages that create viral proteins, but we didn't know that, hidden within the stream of letters we use to denote the genetic information, is a second code governing virus assembly. It is like finding a secret message within an ordinary news report and then being able to crack the whole coding system behind it.

"This paper goes further: it also demonstrates that we could design molecules to interfere with the code, making it uninterpretable and effectively stopping the virus in its tracks."

Professor Reidun Twarock, of the University of York's Department of Mathematics, said: "The Enigma machine metaphor is apt. The first observations pointed to the existence of some sort of a coding system, so we set about deciphering the cryptic patterns underpinning it using novel, purpose designed computational approaches. We found multiple dispersed patterns working together in an incredibly intricate mechanism and we were eventually able to unpick those messages. We have now proved that those computer models work in real viral messages."

The next step will be to widen the study into animal viruses. The researchers believe that their combination of single-molecule detection capabilities and their computational models offers a novel route for drug discovery.

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The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the Engineering and Physical Sciences Research Council (EPSRC). Professor Twarock's Royal Society Leverhulme Trust Senior Research Fellowship and Dr Dykeman's Leverhulme Trust Early Career Fellowship also supported the work.

Further information

Professor Stockley and Dr Tuma are available for interview. Please contact Chris Bunting, Senior Press Officer, University of Leeds; phone: +44 113 343 2049 or email c.j.bunting@leeds.ac.uk.

Professor Twarock and Dr Dykeman are available for interview. Please contact David Garner, Senior Press Officer, University of York; phone: +44 1904 322153 or email david.garner@york.ac.uk.

The full paper: N. Patel et al. 'Revealing the density of encoded functions in a viral RNA,' PNAS (2014) is available to download (URL: http://www.pnas.org/cgi/doi/10.1073/pnas.1420812112; DOI 10.1073/ pnas.1420812112). Copies of the paper are available on request from the University of Leeds press office.

Notes for editors

1. The University of Leeds is one of the largest higher education institutions in the UK, with more than 31,000 students from 147 different countries, and a member of the Russell Group research-intensive universities. We are a top 10 university for research and impact power in the UK, according to the 2014 Research Excellence Framework, and positioned as one of the top 100 best universities in the world in the 2014 QS World University Rankings. http://www.leeds.ac.uk

1.2. The University of York was founded in 1963 and now has more than 30 academic departments and research centres and is one of the UK's foremost universities. It is a member of the Russell Group of research-intensive universities. http://www.york.ac.uk

2.3. The Biotechnology and Biological Sciences Research Council (BBSRC) invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, BBSRC invested over £484M in world-class bioscience in 2013-14. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see: http://www.bbsrc.ac.uk

For more information about BBSRC strategically funded institutes see: http://www.bbsrc.ac.uk/institutes

3.4. The Engineering and Physical Sciences Research Council (EPSRC) is the UK's main agency for funding research in engineering and the physical sciences. EPSRC invests around £800 million a year in research and postgraduate training, to help the nation handle the next generation of technological change. The areas covered range from information technology to structural engineering, and mathematics to materials science. This research forms the basis for future economic development in the UK and improvements for everyone's health, lifestyle and culture. EPSRC works alongside other Research Councils with responsibility for other areas of research. The Research Councils work collectively on issues of common concern via Research Councils UK. http://www.epsrc.ac.uk

5. The Royal Society is a self-governing Fellowship of many of the world's most distinguished scientists drawn from all areas of science, engineering, and medicine. The Society's fundamental purpose, reflected in its founding Charters of the 1660s, is to recognise, promote, and support excellence in science and to encourage the development and use of science for the benefit of humanity.

The Society's strategic priorities are:

• Promoting science and its benefits

• Recognising excellence in science

• Supporting outstanding science

• Providing scientific advice for policy

• Fostering international and global cooperation

• Education and public engagement

For further information please visit http://royalsociety.org. Follow the Royal Society on Twitter at http://twitter.com/royalsociety or on Facebook at http://www.facebook.com/theroyalsociety .

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