Human interferon alpha molecule
[Source: LAGUNA DESIGN/Getty Images]

By William Haseltine, Ph.D., special to Clinical OMICs

Why COVID-19 makes some people so much sicker than others is a puzzle we’re continuously trying to crack. Thanks to two studies recently published in Science magazine, we now know of one very specific predisposing factor: a compromised type I interferon response. This discovery has implications for how we diagnose and treat COVID-19 that could not just reduce suffering, but potentially save lives.

According to the new studies, which analyze data from hospitals around the world, about 14% of COVID-19 patients who go on to develop serious illness lack the ability to either make or mount interferons against invading pathogens. In one study, only 0.3% of the healthy control population had the same deficiencies. While each of the two papers examines a different reason for why this might be, they arrive at the same conclusion—that an absence or dysfunction of interferons might determine the severity of ensuing disease.

Interferons, broadly speaking, are warning signals that alert the immune system whenever an intruder is on sight. Classified as type I, II, or III, these proteins serve a critical defense function in the early stages of infection, quite literally running interference so the host cells can slow viral replication.

The first Science paper studies severely ill COVID-19 patients who have developed so-called “auto-antibodies” against their own type I interferons, reducing the number of interferons circulating in the blood to either extremely low or undetectable levels. These defective antibodies, which block interferons from signaling other cellular defenses into action, represent a certain type of autoimmunity—that is, immunity to substances made by your own body. It has been observed that autoantibodies are more prevalent in older adults than younger, which might explain, at least in part, why COVID-19 is, too.

The second paper focuses on patients who also had minimal to undetectable interferon levels, but whose interferon response was crippled by certain genetic mutations rather than autoantibodies. These mutations, which are also associated with severe influenza, were detected in the DNA of about 3.5 percent of critically ill COVID-19 patients. The control group, characterized by mild or asymptomatic infection, had none. The results echo the conclusions reached by a Dutch study of two sets of brothers who, despite being young and in good health, became critically ill from COVID-19. It was later found that they had inherited a genetic mutation that dampened their interferon response.

It turns out that the SARS and MERS coronaviruses have a number of different non-essential proteins, and a handful of those are devoted to modulating the type I interferon response. For one of them, orf3b, it appears that type I interferons are the primary restraint. In other words, the virus expends much of its genetic energy trying to disable interferon function. These observations, along with the increased susceptibility to severe effects of infection demonstrated in the Science papers, suggest that type I interferons are one of the body’s most important defenses against SARS-CoV-2.

The clinical implications of these findings are threefold. First, we should be screening all identified COVID-19 patients for the auto-antibodies and genetic mutations that might predispose them to severe illness. Healthcare workers and others who are regularly exposed to the virus should undergo the same testing regimen as well. Anyone found to have either deficiency would then know to take extra precautions and receive priority status for vaccinations.

Second, if interferons are critical to our ability to fight SARS-CoV-2 we must treat them as such. While interferon-based drug therapies will likely yield poor results if prescribed to patients with autoantibodies, such drugs could help other vulnerable populations avoid the worst this disease has to offer, including those whose interferon response has been genetically compromised. There may even be a limited role, if given extremely early in cases of acute exposure, for limited interferon prophylaxis, or post-exposure prevention.

The third and final implication relates to another experimental treatment—convalescent sera, or the blood plasma of recovered COVID-19 patients, authorized in the United States for emergency use. Potential plasma donors must not only be screened for auto-antibodies against interferons, but also be removed from the donor pool if they test positive. Their plasma might otherwise unwittingly debilitate a recipient’s immune response. This applies as well to the donors selected to prepare hyperimmune globulins, or hyperimmune igG, a more purified and potent concentration of plasma.

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