Magic cap lifted

If we are attacked by viruses, the guardians of our immune system act quickly and efficiently. Within a very short time they release - among others - the messenger substance interferon, which alarms the entire immune system and directs the immune response in the right direction. Most of the time. Sometimes viruses succeed in undermining these mechanisms and we become ill. Scientists at TWINCORE have now succeeded in identifying the information loops that a particularly well-camouflaged virus uses to undermine the immune response. The cytomegalovirus from the herpes virus family camouflages itself, among other things, by making its host blind to the interferon alarm signal.

"In order to understand what the immune cells of the first line of defence respond to, we looked at three different cell types and infected them with the particularly tricky cytomegalovirus," says Dr Marius Döring, a scientist at the Institute for Experimental Infection Research at TWINCORE. He has investigated two different dendritic cell types and macrophages that wait for intruders in the body. Their task is to show these intruders to other cells of the immune system and thus pass on the information to the second line of defence of the immune system.

"We asked ourselves how the individual cell types react to the virus independently of each other in order to better understand this early reaction of the immune system," says Marius Döring. "Because it sets the course for a successful defence against the pathogen." To answer this question, the researchers treated the immune cells with cytomegaloviruses in different states: with completely normal viruses that effectively disrupt the immune cells; with viruses killed by UV light, which only consist of their envelope, so to speak, but can no longer actively influence the immune cells, and with viruses that lack a special gene. Without this gene, the viruses are no longer able to suppress the interferon signals in the host cell. This virus has been deprived of its interferon cloak, so to speak - but the virus also has various other cloaks for other signalling pathways that influence the immune system and slow down the immune response. This allows the researchers to assess what role the interferon signals in these cell types in particular play in the defence against the cytomagaly virus.

The experiments have shown that it is precisely this interferon cloak of invisibility that plays a special role in controlling the immune response: While the intact virus triggers the - expected - slowed reaction in a part of the immune cells, the virus killed with UV light induces a strong initial defence reaction in these immune cells. And the genetically manipulated virus, from which only the interferon camouflage cap was removed, also triggers a similarly strong interferon reaction in the affected immune cell types. "This shows that an intact virus inhibits the entire defence cascade simply by switching off the interferon signalling pathway. What's more, the initial release of interferon triggers and intensifies further interferon release in other cells, so that a veritable wave of messenger substances rolls through the attacked organism," explains the biologist. As the virus nips this wave in the bud, so to speak, the immune system can only react weakly to the pathogen. "This feedback loop - the self-reinforcing interferon response - is essential for a successful immune defence," concludes Marius Döring. "We were able to show for the first time that the cytomegalovirus interrupts this feedback loop in immune cells and can reduce the strength of the host's early immune response." This result is a first step towards the development of a therapeutic vaccine against cytomegalovirus - which can be used after the patient has already been infected with the virus and which activates the immune system against the virus.