1st June 2017

The Molecules of Life That Trigger Death

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Layal Liverpool, DPhil in Infection, Immunology, and Translational Medicine

Nucleic acids –  DNA and RNA – are the molecules of life. Without them we wouldn’t exist but, ironically, they are the very molecules used by viruses to hijack our cells.

Viral nucleic acids act like a virus-blueprint, containing all the instructions necessary to make more viruses. But there is a problem. The machinery required to carry out these virus-making instructions is only found inside living cells. This is because viruses are hundreds of times smaller than our cells and so simply don’t have the space to carry around bulky machines. So, instead they invade and hijack our cells and, unfortunately, make us sick in the process.

Luckily, our cells have developed numerous defence strategies against unwanted invaders like viruses. One of these strategies is to commit cell suicide. This might sound paradoxical at first but in fact by destroying itself, the cell eliminates the machinery a virus needs in order to replicate and spread. This noble sacrifice stops the spread of the virus to the rest of the body, protecting us from disease.

And these cells do not die quietly! They commit suicide in a loud and explosive way, which has an added benefit: it alerts the immune system. Our immune cells respond to the cry for help and, just like a highly-targeted SWAT team, rush to the site of infection armed with powerful anti-viral weapons.

This defence strategy is somewhat risky though; if too many cells commit suicide this could also make us sick. Indeed, there is a delicate balance between the successful elimination of virus-infected cells and the inappropriate destruction of healthy cells. To achieve this, our cells rely on special proteins called sensors whose task it is to detect invading viruses and trigger immune responses to eliminate them. Just as a smoke alarm detects the smoke coming from the fire, these virus sensors work by detecting the nucleic acids from the virus as a sign of the infection.

These sensors have a tricky job, however, as they need to distinguish the viral nucleic acids from our own genes, which are also made of nucleic acids. Failure to do so could result in auto-immune diseases, in which the immune system attacks and causes damage to healthy host cells.

Given how critical this self/non-self discrimination is to the balance between health and disease, scientists are working hard to better understand this process. Understanding exactly how these sensors recognise viral nucleic acids and distinguish them from our own could allow us to intervene in this process therapeutically. For example, to boost anti-viral immune responses in people with viral infections or to suppress them in people suffering from auto-immune diseases.

So how can cells tell the difference between viral genes and our own nucleic acids? Excitingly, scientists recently discovered a new way in which cells sense virus infection and then commit suicide in response. Their discovery is based on a curious property of nucleic acid: their ability to change shape. One of these is a zig-zag shape creatively named ‘Z’. Z-DNA and its molecular cousin Z-RNA were discovered decades ago but noone fully understood what their role was.

It has now been revealed that these zig-zag nucleic acids may be a sign of virus infection. Jonathan Maelfait and colleagues in Jan Rehwinkel’s laboratory at the University of Oxford, found that one of the sensors inside cells specifically recognises the zig-zag shaped nucleic acids during virus infection and activates cell suicide.[1]

The next steps will be to investigate the role of this sensor in the detection of medically important viruses such as flu and HIV. It will also be important to study the impact of the ultimate sacrifice, cell suicide, on other anti-viral immune responses such as the release of antibodies, which can destroy virus particles outside of cells.

Viruses, although themselves not living, are able to hijack our cells using the very molecules that give life. Ironically, the detection of these molecules through the recognition of their unique zig-zag shape can end in death. Death of virus-infected cells eliminates them and the viruses they carry from the body, preventing disease.

[1] This study had not yet been published at the time of writing.

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