Scrambled genomes
Passionately interested in new pet animals, Frédéric Gandar decided to go against the grain of scientific disinterest with regard to this problem. When he began sequencing the genome of TeHV-3, he did not know what he would find. And, actually, what he found was meaningless. The strain he was working on – the one that all scientists use – didn’t seem to make any sense. It took him two years to understand that, in reality, it was not a strain but rather a mixture of three different strains having all an incomplete genome.
Another complication entered the mix. “When a genome is sequenced, the sequences obtained must be organised. Obviously, we always have the reflex to attach whatever we discover to what is already known. Here, we could not join all the “jigsaw pieces” that were known in established models. Nothing seemed to fit and there was always a piece of the puzzle missing”, recalls the young researcher. All 250 herpesvirus genomes studied up to date – these include viruses that affect oysters as well as humans – are classified according to six distinct genomic structures. All, that is, except Testudinid herpesvirus 3 (TeHV-3). Frédéric Gandar and Alain Vanderplasschen could not believe what they were seeing but they had in fact just discovered a new genome structure. This structure would be the seventh. “Virology reference books will have to be updated! Who would have believed that a virus affecting tortoises would reveal such a thing”?
The TeHV-3 had not yielded up all its secrets however. When the researchers realised that they were dealing with a mixture of three different strains, they tried to separate them from each other in order to know whether they were still capable of replication in isolation. This seemed very unlikely as these strains had been “deleted”, they were missing large sections of the genome from 12,000 to 22,000 base pairs. “It was a bit like having a car weighing 100 kilos and then removing 10 or 12 kilos of matter”, explains Alain Vanderplasschen by way of comparison. “It is unlikely that the car would still work”.
“Surreal as far as viruses are concerned”!
And yet, the strains continued to multiply as though everything was normal. Not only did two of them appear to be capable of infecting, but also of causing death. “This is surreal as far as viruses are concerned! Large pieces of the genome are missing but this still does not prevent the virus from killing its host”. The third, however, did not seem to be faring so well. In cell-culture, it continued to proliferate without any problem but in the tortoise, on the other hand, it was unable to invade the animal!
This was fortunate. Thanks to this third strain Frédéric Gandar will probably be able to create a vaccine. The next step will be to inoculate the tortoises with this form of the virus to see whether their immune system will develop an immune response which could ultimately protect them from lethal attacks once they have been infected. “In the coming year, we will find out if we have a vaccine”.
The discoveries could have stopped there and would undoubtedly have been enough to merit publication in the prestigious Journal of Virology but Testudinid herpesvirus 3 led to other discoveries. The first of these discoveries concerned “immune evasion”. This is a characteristic that is common to all viruses: they steal genes from the animal they infect at different moments during evolution. TeHV-3 had managed to steal a gene for an interleukin-10 (IL-10), a molecule which serves to reduce inflammation. The immune system must trigger mechanisms that fight against pathogens as soon as their presence is detected. Inflammation is one of the mechanisms. It is vital for the organism to stop these anti-pathogen mechanisms as soon as they are no longer necessary. This is comparable to a firefighter who must turn off the water as soon as the fire has been extinguished in order to prevent further damage to things that were not destroyed by the fire. Interleukin-10 is a molecule that calms the response of the immune system. “The virus therefore stole this IL-10 so that when it invades the organism the immune system should be triggered but this protein inhibits its activation. This phenomenon was quite well-known but had never been described in this virus sub-family”, explains Frédéric Gandar. Even more astonishing: the structure of the interleukin-10 stolen from the tortoise is very similar to that found in humans. When one is superimposed on the other, you get a near perfect match.
