Overactive arm of the immune system linked with long Covid

To SARS-CoV-2, the viral cause of Covid-19 now, and we’re going to take a closer look at the stubborn persistence of COVID-19 symptoms. It’s frequently called long COVID, and new analysis of blood samples from patients suggests that we might be closer to understanding what leads some people to develop it while others recover from the virus more quickly. Here’s Professor Onur Boyman from the department of immunology at the University of Zurich…

Onur - Long Covid is actually a combination of different symptoms. While we understand these symptoms, we don't understand actually how they are caused or what keeps them active. We said, let's measure a lot of proteins in the blood of patients that have long covid and then let's inquire what is different between those that have long Covid compared to those that don't.

Chris - Is the sort of rationale behind this then that if you look at enough people enough times and you look at enough different chemicals, you can spot patterns that keep coming up in people who do have the problem and are not there in the people who don't have the problem. And that argues that those changes must in some way be linked to the problem?

Onur - That is correct and that's exactly what we did. And then we asked, what is the most different protein, or protein group between long Covid patients and those that don't have long Covid.

Chris - And what is it? What is the biggest difference?

Onur - We found that an arm of the immune system is actually overactive in patients that have active long Covid. It's actually a very interesting part of the immune system. It's called the complement system, which usually should be activated when we have an acute virus infection and should then go back to its normal state. In long Covid, this return to the normal state is not happening. And what this then causes is a state where the body and many of the body's cells, not only immune cells but normal cells, are in an alarmed state.

Chris - Were you able to look upstream of the Covid infections in these people in order to reassure yourself that it wasn't like that already and that it's that that makes people more susceptible to getting long Covid versus long covid, is this happening?

Onur - That's very true. So then the question of course is how can we test whether this is a cause or a consequence of their symptoms? So what we then did is compared Covid patients which either did not have any long Covid at all, or got long Covid but then recovered, versus those in whom long covid persisted. And what we could see is the complement system recovered in those which recovered from their symptoms and always at the same time.

Chris - If it's staying high, the level of this is staying active all the time, something must be driving it. It's like a switch has been thrown. So what do you think's doing that? How is that being achieved?

Onur - Yes. So, initially we think it gets activated by the virus, but then why doesn't it switch off there? We think there are loops and signals that keep it active in patients that suffer from long Covid.

Chris - It's almost like someone's turned the thermostat up and the temperature set point is now higher, so the room ends up hotter. Is there a way of turning that thermostat back down? Can we detune the immune response back down again to where it should be in these people?

Onur - That's, of course, a very important question. Some individuals seem to be able to turn it down. So if we take someone who had Covid and then long Covid and spontaneously recovers, this complement activation, it's normalised, and the symptoms go away. Why that is the case? We don't know. On the other hand, if somebody does not recover and keeps on having this complement activation turned on all the time, then another possibility would be to use specific drugs that actually act on tuning down the complement system.

Chris - Given that you've got what appears to be a sort of molecular fingerprint for someone with long Covid, could this be the basis of a test then? Because that's been the other thing that's proved a bit elusive is helping people to get a diagnosis to account for their symptoms, give them the reassurance that this is what's going on, and then obviously manage their symptoms for them. So can we use this as a test?

Onur - This is a possibility. We've identified a central piece in the puzzle to understanding long Covid, a mechanism that unifies the different findings that had been collected previously. This can of course help diagnose long Covid better and hopefully in a second step it might actually also provide new targets for treatment.