Norman Swan: One of the mysteries surrounding COVID-19, the disease that is caused by SARS-CoV-2, is why some people experience severe life-threatening disease and others don't. Age, male gender and having other problems like diabetes, heart and lung disease and probably obesity, are risk factors. But what about individual differences in people's immune systems? Well, two recent studies have found that to be the case in a significant percentage of people with serious COVID-19 disease. One study looked for genetic patterns and found an effect on immune messages called interferons. There are about 18 interferons in the body and they act like volume controls and orchestra conductors in the immune system once it has been alerted to an attack by a virus. The second study found antibodies against interferon in some people. This has huge implications for a better understanding of the immune system, not to mention more targeted therapies for people with COVID-19. Professor Paul Hertzog is one of Australia's leading experts on interferons. Paul is head of the Centre for Innate Immunity and Infectious Disease at the Hudson Institute in Melbourne.

Paul Hertzog: This study, initiated by Jean-Laurent Casanova who is based at the Rockefeller, and Helen Su at NIH, they've set up actually a global network looking for patients who might have genetic predispositions to getting extremely ill with the Covid SARS-CoV-2 virus. And it is really the first output of that global network of people who are doing the searches.

So firstly it's really the first substantial report that there is a genetic susceptibility of this disease. It's something that we always suspected but this really proves it. And more particularly what is unusual and fascinating is that most of the culprits they found were actually lying in different components of the interferon signalling system.

Norman Swan: They found a relatively consistent genetic problem in people when they looked at their genes, and these genes seem to code for the interferons in some shape or form.

Paul Hertzog: Yes, they identified 12 genes that we knew were involved in susceptibility to infections, particularly respiratory infections, and they happen to be in the interferon pathway, but involved in the production of it, or the response to it. And so they really looked where the light was and they said, well, can we find deficiency in any of these 12 genes? They actually found deficiencies in quite a high proportion of patients, about 3% of them. So I'm sure there are many more to cover because this was really just a very targeted look.

Norman Swan: So 3% doesn't sound too high.

Paul Hertzog: With a million people dying, I think it's a lot of human beings. And I think it is just the tip of the iceberg.

Norman Swan: People have been talking about interferons now for a while, and in fact interferons have been trialled as a treatment for people with COVID-19 disease even prior to these studies coming out. What's the net effect of these genetic abnormalities or these genetic differences?

Paul Hertzog: I suppose what they might enable us to do, Norman, is to use what you would call a precision medicine approach where we can identify people who would benefit and who would not benefit from this. So, for example, if a person has a defect which means they are unable to respond to interferon, and some of these genes are involved in that, it's absolutely pointless giving them interferon therapeutically because they just would not be able to respond. On the flipside, if we identify patients who can't make it and some of the genes are involved in the making of the interferon, then they are more likely to benefit from therapeutic administration of interferon.

Norman Swan: So where does this research go next? Presumably it's a simple test or what?

Paul Hertzog: I think that's a simple test. As I said, I think it might enable us to identify groups of patients who are likely to respond to interferon than those who don't. And if we can talk for a minute about the other paper which involves the identification of autoantibodies to interferon, that's probably in fact a far more fascinating study because autoantibodies, some of your listeners might recognise, are usually associated with autoimmune diseases like lupus where something goes wrong with the immune system, instead of recognising a foreign antigen it turns on itself, and these rogue antibodies can cause disease. So what they found in their second study was that 10% of the patients they looked at, which is a staggering number really, produced antibodies to these type I interferons and would negate its effect. That population of patients won't be able to respond. That has a number of implications. Secondly,

Norman Swan: Before you get to the implications, is the assumption that the autoantibodies pre-existed the infection or were created by the virus?

Paul Hertzog: Their study was nearly 1,000 patients, so there were probably about 100 of them and that they found these autoantibodies. I think in about 10 or 12 of them that they had the opportunity in the samples there to look before they had obvious signs of disease, and some of them did have pre-existing antibodies, but that's just a small proportion of those patients, I think it needs a much bigger study but it tells us that some of them certainly can predate. And that's interesting for a number of reasons because it identifies an underlying condition that we never would have thought of. And the other thing is those patients have no previous signs of other respiratory or susceptibility to viral infections, which raises the question whether this is fairly specific to COVID-19.

Norman Swan: And it also raises a question which a lot of people, at least to my Coronacast podcast ask, if I've got rheumatoid arthritis or Multiple Sclerosis or scleroderma or SLE, one of the other autoimmune diseases, doesn't make me more susceptible to COVID-19? Do any of the other autoantibodies that are around in the community affect interferons in this way?

Paul Hertzog: A really interesting question that has complicated answers, and the answers are yes and no. There are some autoimmune conditions where similar autoantibodies to interferons have been seen. But there are others like lupus where the opposite seems to happen. In lupus it seems a large part of the disease is driven by interferon, and in fact there was a large trial headed by an Australian clinician from Monash, Eric Morand last year that identified blocking antibodies to interferon that actually look like they will have beneficial effects in lupus, so that's quite the opposite effect.

Norman Swan: So this discovery of autoantibodies which might actually be quite significant in a reasonable percentage of people, is there a therapy there?

Paul Hertzog: Good question. Not obviously. It's probably may lieagain, if you're thinking interferon therapy it clearly wouldn't work and less there is some specificity in the antibodies that you could get around. I think there are ways of screening it out. For example, you wouldn't want the samples of those serum in your convalescent serum preparation, so I think there are practical outcomes like that.

Norman Swan: Oh yes, that's right, so if you're taking serum from these people to give to other people and you give them autoantibodies you can make them worse.

Paul Hertzog: Right, so it's another screening test for that. There are B cell and antibody depletion therapies that are used in other autoimmune diseases, and that might be in the area that could be looked at in these patients.

Norman Swan: So what's next for your research, given all this?

Paul Hertzog: Well, it provides us with an opportunity. For us it's yet another example of the importance of the interferon system. We are currently collaborating with Jean-Laurent Casanova in a number of these mutations prior to Covid and we will continue that. What we'll do is drill down to try and find out the mechanism whereby some of these mutations in the interferon system are working, and in fact whether some of them that haven't yet been identified as loss of function and disease contributing might in fact be so.

Norman Swan: Paul, thanks for joining us.

Paul Hertzog: My pleasure, thanks a lot.

Norman Swan: Professor Paul Hertzog is head of the Centre for Immunity and Infectious Disease at the Hudson Institute in Melbourne.

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Could genetics explain the mystery of severe coronavirus? - ABC News

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