At first glance, the cause of severe infectious disease seems obvious: The culprit is a bacterium, a virus or some other pathogen. Yet this can’t be the full story. After all, there are plenty of differences in a given pathogen’s effects from one person to the next, notes Jean-Laurent Casanova, a human geneticist of infectious disease at Rockefeller University. This clinical variability, he says, “is the fundamental infection enigma.”

Various factors contribute. Another disease or condition may have made the body more vulnerable, or the immune system may have weakened with age. And maybe one person got a larger dose of the pathogen than another did. But according to Casanova, the enigma is something beyond that. Time and again, he has seen children who are seriously ill from infections that left their relatives untouched. And over the past 25 years, he and his colleagues have shown that severe infectious disease symptoms can often be related to uncommon variations found in patients’ genes.

Some of these genetic variants (small differences in bits of DNA) cause “primary immunodeficiencies” that make people vulnerable to many different infections — because, for example, they don’t produce white blood cells called lymphocytes that protect against a range of pathogens. In other cases, people may be more vulnerable to severe illness caused by a particular group of microorganisms, such as the mycobacteria that cause diseases like tuberculosis, or the herpes simplex virus, which causes mild symptoms in most people but deadly encephalitis in some.

As the Covid-19 pandemic roils on, Casanova and others are finding genetic variants that help to explain the differing reactions to SARS-CoV-2 — from absent or mild symptoms all the way to serious sickness and death. And yet again, facets of the immune system appear to be involved — notably, a set of signaling molecules called interferons.

Not just the germs

The germ theory of disease, established in the late 1800s, revolutionized human medicine, ultimately ushering in a bevy of advances such as the development of antibiotics, antivirals and vaccines as well as public health measures to prevent infections and their spread. But Casanova and his colleague Laurent Abel argue in the Annual Review of Pathology: Mechanisms of Disease that the success of germ theory may have eclipsed the importance of genetic variability in our species.

Clearly, there can be no infectious disease without a pathogen. “You need to be exposed, of course,” says Abel, a human geneticist at Inserm in Paris, “and the intensity of exposure may play a role.” But even when all things seem to be equal, a great deal of variability in people’s responses often remains, he says. And the reason for that, Abel and Casanova hypothesize, often lies in the genetics of our immune response, and what researchers call inborn errors of immunity.

The term doesn’t necessarily imply that a genetic variant causing severe disease is bad across the board. Though it might make a person vulnerable to severe disease caused by one pathogen, it might provide better protection against another, or lower the risk of inflammatory disorders caused by hyperactive immune systems. Last year, for example, Abel, Casanova and colleagues reported that possessing two copies of a certain variant of a gene called TYK2 makes people more likely to develop tuberculosis after infection with the bacterium that causes it. That same gene variant offers protection against rheumatoid arthritis.

The usual suspects

Now these scientists and many others have turned their attention to Covid-19, gathering large amounts of data on people who are known to have contracted the SARS-CoV-2 virus. Although more than a million people have died from the disease, many others have demonstrably been infected without any symptoms at all. Might certain inborn errors of immunity help to explain these differences — and could such understanding help physicians more effectively prevent or treat severe symptoms?

Together with immunologist Helen Su of the US National Institute of Allergy and Infectious Diseases, Casanova led a consortium to investigate this question by comparing the genomes of 659 patients with life-threatening cases of Covid-19 pneumonia to those of 534 infected people who did not need hospitalization and developed mild or no symptoms. The scientists had candidate genes in mind, Casanova explains: “The starting point was to test the idea that the genes known, when mutated, to underlie life-threatening influenza could also underlie life-threatening Covid-19,” he says. The study, published in Science in September, revealed that the genomes of at least 23 of the 659 severely ill patients had an unusual variant in one or the other of eight such genes the scientists examined.

The researchers also showed that half of these variants impaired the activity of the gene such that little or none of the protein it codes for is made. The other variants resulted in abnormal proteins. And since all eight genes and their proteins are involved in the production of, or affected by, an important class of immune-system molecules called type I interferons, this suggests that these are involved in Covid-19 susceptibility, the scientists reasoned. Type I interferons can be made by nearly any cell in the body in response to viral exposure, helping to ward off infection in a variety of ways. With fewer interferons around, a virus might be more apt to cause dangerous disease.

Misguided immunity

But there clearly was more to the story: After all, these gene variants showed up in just 3.5 percent of patients with critical Covid-19. So Casanova and colleagues explored another lead inspired by earlier work they’d done — related, yet again, to interferon molecules. Some people, it turns out, make antibodies against their own interferons, which removes the interferons from circulation almost as soon as they are produced. In a second study of Covid-19 patients also reported in Science, Casanova, Abel and colleagues reported that at least 101 of 987 patients with severe symptoms carried antibodies in their blood against one or more type I interferon.

The researchers are now looking at many other genes that affect the activity of type I interferons, and whether production of antibodies that target other immune molecules may explain severe Covid-19 in other patients. In the meantime, they hope that their findings might inspire treatments for people who are especially vulnerable to the virus.

If patients are making antibodies against interferons, those antibodies or the immune cells that produce them could be removed using a technique called plasmapheresis, where blood plasma is removed, treated and then reinfused, the scientists suggest. And when plasma from patients who have recovered is transferred to other patients — an experimental procedure that aims to supply critically ill people with antibodies from recovered patients — it should first be checked for the presence of interferon-removing antibodies, they say.

If patients are found to have gene variants that impair the production of type I interferons, Casanova and colleagues suggest that they might be helped with interferon infusions, an approach that has helped people with interferon-related inborn errors of immunity in the past. Will it work for Covid? “I do not have a crystal ball,” Casanova says, but he believes it should be tested. Findings may come soon: Several studies investigating interferon infusions for people with severe Covid-19 were already underway before the Science papers were published.

Silence before the storm

That some severely ill patients lack type I interferons certainly suggests that supplying them might help. But other research indicates that things might be more complicated — and that timing could be crucial. A study published in July in Nature tracked the immune response of 113 Covid-19 patients in Yale New Haven Hospital, finding that many hospital patients with high levels of type I interferons had longer hospital stays and were more likely to die — just the opposite of what one would expect if type I interferons were helpful. Furthermore, the amount of type I interferons tended to drop over time in patients with moderate symptoms, whereas it remained high in patients with severe disease, suggesting that more interferon is not always better.

Though this may seem paradoxical at first sight, it could be explained by the fact that type I interferons are most important at the very start of infections, says Saurabh Chattopadhyay, a viral immunologist at the University of Toledo in Ohio.

Most of our cells begin making interferons after a virus binds to the cell surface and then tricks the cell into engulfing it. The interferons then go on to activate hundreds of different genes, as Chattopadhyay and his colleagues outline in an article in the Annual Review of Virology. These serve to protect the cell in an array of ways — such as stopping the virus from multiplying its genetic material, warning other cells of imminent viral attack and calling immune cells to the area.

If everything goes well, this flurry of early activity might nip a viral outbreak in the bud. If not, things might get out of hand. As more cells are infected and more of our tissues are affected, the immune response can escalate — damaging rather than rescuing tissues and causing dangerous immune overreactions that are sometimes termed cytokine storms. In other words, by the time a person ends up in the hospital, the virus has already spread, and at that point, the production of interferons may be harmful.

Interferons, Chattopadhyay says, “do all sorts of good stuff as well as a lot of bad stuff,” depending on the nature of the virus and the tricks it has evolved to get past human defenses.

The more scientists learn about what makes some of us vulnerable to Covid-19, the better chance they have of developing therapies. So as well as investigating likely contenders such as the interferons, researchers are looking beyond the usual suspects for other genetic variants associated with severe disease, hoping to find additional important players.

And they seem to be unearthing them. One such study published in October in the New England Journal of Medicine reported that people with blood group A have an increased risk of severe Covid-19, while those with blood group O have a decreased risk. Most intriguingly, a cluster of genetic variants in a part of chromosome 3 (which, it turns out, some of us inherited from Neanderthals) seems to increase Covid-19 vulnerability. That region contains six genes, and at least five of them relate to immune activity. The actual culprit is yet to be determined.


10.1146/knowable-110320-2 | This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

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