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The immune system

Knowing your enemy: viruses as the Trojan Horses of our immune system

It’s that time of year when we all seem to pass around the same cold; everyone seems to be sniffing a bit more than usual, or suffering from that irritating cough that you just can’t get rid of. A cold is just one of many ailments caused by viral infections, and although it might not always feel like it, your immune system is constantly fighting these viruses. But how does a cell know when it’s infected? New research from Jan Rehwinkel’s lab, published in Science earlier this year, shows that infected cells can in fact hijack the viruses themselves to help the body fight against them. Intrigued? Alice Mayer explains more…

Our immune system protects us against various infectious agents, including bacteria and viruses.

A cell infected by a virus will release signalling molecules called type I interferons (IFNs). These molecules act on neighbouring cells to prevent further propagation of the virus. They also contribute to a process that leads to the killing of infected cells and to the production of antibodies. It is therefore critical for cells to induce IFNs as early as possible upon infection.

But how can a cell detect a viral infection? Cells express receptors that detect “molecular signatures” of viruses. In particular, viral nucleic acids (DNA and RNA) are recognised as a sign of infection, either because they are present in a cellular compartment that doesn’t normally contain these nucleic acids, or because they have features that are different from those nucleic acids normally produced by the cell.

The type of DNA or RNA molecule detected varies between different viral infections and cells have several receptors that can detect different nucleic acid structures from a range of different viruses.

Cyclic GMP-AMP synthase (cGAS) is one of these receptors and detects viral DNAs. Discovered only recently, cGAS uses a distinctive signalling pathway to induce type I IFNs. While other receptors signal via the interaction between different proteins, cGAS – once activated by the presence of viral DNA – catalyses the formation of a small molecule called cGAMP (cyclic GMP-AMP).

cGAMP moves freely in the cell and interacts with another protein, the Stimulator of IFN Genes (STING), to induce the production of type I IFN. Of note, the ability of cGAS to sense viruses is not limited to DNA viruses as cGAS can also detect some retroviruses as HIV-1.

Once HIV infects a cell, its RNA genome is copied into a DNA molecule (cDNA) which will then be integrated into the cell’s own genome. It has been shown that HIV-1 cDNA can be detected by cGAS. However, the copying process takes place within the virus capsid, a protein shell surrounding the viral nucleic acids. Therefore, the cDNA should be hidden and not accessible for detection by cGAS.

During a discussion about this question at one of our Journal Clubs, an idea developed: what if cGAS was packaged inside the virus during replication and travelled to newly infected cell as part of the virus so that it could detect the cDNA of the virus as soon as the copying process starts? The product of cGAS – the small molecule cGAMP – might then be able to exit the capsid due it small size and activate STING.

Essentially – this system would act as a Trojan horse, with cGAS being sent by the host’s own cell, to alert the next cell that it has been infected by making cGAMP.

summary

When some viruses infect cells, the cellular protein cGAS detects viral DNA and initiates the formation of cyclic GMP-AMP (AG). This second messenger incorporates into newly formed progeny viruses. Upon subsequent infection, cGAMP is released into newly infected cells and rapidly activates an antiviral response.

 

Our lab set out to investigate this idea, with support from the MRC Human Immunology Unit and the Wellcome Trust.

As it turns out, although the Trojan Horse theory was right, it’s actually the second messenger cGAMP, and not the DNA sensor cGAS, that is packaged up with the virus and alerts the newly infected cell.

In a paper recently published in Science, we demonstrate that cGAMP is incorporated into viral particles. Upon infection of new target cells, cGAMP is released into the cell and rapidly stimulates the production of type I IFNs. This process allows cells to detect the virus quicker and therefore initiate a better and faster anti-viral immune response.

In addition, these findings could potentially be used to improve vaccination protocols. Viruses can be engineered to target a specific cell type and can potentially be used to therapeutically target cancer cells. Loading of cGAMP in these viral vectors could therefore boost the immune response induced against tumour cells and improve current vaccination strategies.

We are currently investigating these lines of enquiry further to try to harness this Trojan Horse – and use it for our own good.

Post edited by Bryony Graham, Lauren Howson, Aimee Fenwick and Jan Rehwinkel.

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