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Exploring the family of interferons for clues about COVID-19 and its treatment

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes symptoms called coronavirus disease 2019 (COVID-19). In many people who become infected with this virus, perhaps as many as 40% have no symptoms of infection. However, a portion of people develop symptoms that can resemble a flu. In a smaller proportion of people, the symptoms can become severe and include breathing problems and pneumonia.

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Interactions between SARS-CoV-2 and the immune system underpin the body’s response to this virus. In this issue of TreatmentUpdate, we bring together emerging research that outlines some of the immunological events that occur during infection with coronaviruses. Learning about these events can be useful in understanding why some potential treatments, such as members of the interferon family, are being tested against the pandemic coronavirus. Delving into the immunology of SARS-CoV-2 may help explain some of the complications that arise in people with COVID-19.

Enter the virus

Cells lining the nose, throat and upper part of the lungs are usually the first places in the body where germs that are inhaled are encountered by the immune system. SARS-CoV-2 enters cells using a protein (or receptor) found on the surface of cells called ACE2.

Once inside a cell, the presence of the virus should trigger the cellular equivalent of multiple alarms. Cells have internal sensors that are supposed to detect invading germs. If these sensors detect SARS-CoV-2, they trigger a series of events that quickly leads to the production of molecules, particularly ones from a family used for sending signals. These molecules are called interferons.

Getting to know the interferons

There are three main types of interferons:

  • Type 1 – interferon-alpha and subtypes such as interferon-alpha-1, 2, 3 and so on; interferon-beta and subtypes; and several less-studied interferons such as interferon-delta
  • Type 2 – interferon-gamma
  • Type 3 – interferon-lambda and subtypes such as interferon-lambda-1, 2, 3 and so on

To respond to interferon, cells need to have a protein on their surface called an interferon receptor. Some of these receptors are sensitive to one type of interferon, while other receptors are sensitive to other types of interferons.

How interferons work

A greatly simplified explanation of how interferons work in the initial stages of viral infection follows. Once interferon is produced, it triggers genes in a cell to make proteins that do the following:

  • limit the ability of infected cells to produce copies of SARS-CoV-2
  • let other cells near the infected cell know that a viral invasion is underway and that uninfected cells can take steps to protect themselves
  • activate cells of the immune system so they can come to the help of the infected cell
  • help sentinel cells of the immune system learn the identity of the invading germ
  • enhance the functioning of T-cells, such as CD4+ and CD8+ cells, which can release antiviral substances that destroy virus-infected cells

Timing is everything

Scientists who study viruses and the immune system have said that “the timing of interferon production is crucial for its influence on the immune response to virus infection.” That is, interferon production needs to be triggered very early in the course of viral infection for the best results in limiting the spread of infection.

Viruses and SARS-CoV-2

As interferon is such an important part of the immune system’s defence against viruses, these germs have evolved ways of interfering with the activity of interferon.

Scientists who have carried out lab experiments with cells and SARS-CoV-2 have found that this virus can somehow weaken or delay the production of interferon.

Some studies have found that in people with moderate and severe COVID-19 sometimes there is hardly any detectable interferon present. In some experiments, very low or absent levels of interferons in the blood have coincided with high levels of SARS-CoV-2 in people.

Looking at SARS-CoV-1 for clues

In 2003 there was an outbreak of severe pneumonia (SARS) caused by the virus SARS-CoV-1. Analysis of this virus found that it carried instructions in its genetic material to make many proteins that interfered with interferon. These viral proteins had the effect of limiting interferon production and activity.

SARS-CoV-2 has about 82% similarity to SARS-CoV-1. It is very likely that SARS-CoV-2 also carries instructions in its genetic material to make similar proteins that weaken and limit interferon’s production and activity. Although preliminary results from lab experiments suggest this, these findings require confirmation.

Friendly fire and defective genes

In one large study of about 1,000 people with COVID-19 pneumonia, researchers found that about 10% had antibodies that attacked and disabled interferon. These anti-interferon antibodies were present in blood samples taken from some of the participants in the pre-COVID-19 era. This suggests the possibility that SARS-CoV-2 infection did not trigger the production of antibodies that attacked interferon. In this study, most people (94%) with these antibodies were men. The age of people with the antibodies in their blood ranged from 25 to 87 years. However, 50% of participants were between 65 and 87 years. Participants were from different continents and a range of ethno-racial groups. The form of interferon attacked by the antibodies was interferon-alpha.

Another study has found defects in the genes that produce interferon-alpha in some people with severe COVID-19. The researchers compared genes from 659 people critically ill with COVID-19 and genes from 534 people infected with SARS-CoV-2 who were either symptom free or who had mild symptoms. In about 4% of critically ill people, there was very little interferon alpha in their blood and these people had defective genes.

Taken together, the findings from these two studies can probably explain why about 14% of people who are infected with SARS-CoV-2 have severe symptoms.

Emerging research suggests the possibility that antibodies that attack interferon may affect more than 14% of people with severe COVID-19. However, such emerging research is controversial because it has not been embraced by many scientists and requires firm evidence to prove its findings.

Attacking antibodies

The presence of antibodies that attack interferons was first detected in the 1980s in some people with the autoimmune disease lupus who were treated with interferon-alpha and interferon-beta.

The findings from studies in people with severe COVID-19 are intriguing and surprising and should serve as a starting point for much more research focused around the following questions and issues:

  • Why do some people with COVID-19 have antibodies that attack interferon-alpha; do they serve a useful purpose?
  • How widespread is the issue of antibodies that attack interferon-alpha?
  • Are antibodies that attack interferon-alpha common in older people?
  • Are antibodies that attack interferon-alpha linked to other health problems such as increased susceptibility to other viral infections and cancer?
  • In people with COVID-19 who have antibodies that attack mostly interferon-alpha, why do the antibodies not attack other interferons?
  • The previously mentioned studies assessed interferon levels in the blood. It might be useful to assess interferon levels in the lungs.

New approaches

In theory, it is possible to develop counter-measures to help people with COVID-19 who have antibodies that attack interferon. For instance, some researchers have suggested filtering the blood of people with these antibodies, in the hope of removing them. However, such filtration does not address why the antibodies developed in the first place or which subset of B-cells made them. If the antibody-producing cells are not removed, presumably they will keep making antibodies that attack interferon.

It is noteworthy that the vast majority (98%) of antibodies in the previous studies attacked the interferon-alpha family and the remaining 2% attacked interferon-beta. About one-third of people with these antibodies who developed pneumonia died. Therefore, it may be helpful to test other members of the interferon family, such as the following, in people with severe COVID-19:

  • interferon-beta
  • interferon-lambda

Early vs. late use of interferon

Experiments with cells and animals suggest that, in general, interferons play a key role very early in the viral infection process. In the early stages of infection, interferons appear to help elaborate a number of useful defensive activities. However, in later stages of infection, large amounts of interferon may not be useful and may even contribute to harm.

Lab experiments with animals suggest that when type 1 interferons are given late in the course of disease, these interferons can cause the immune system to release chemical signals that suppress the body’s ability to fight infections. This can happen in a number of different ways, including weakening the ability of CD8+ cells to attack virus-infected cells and even stimulating large numbers of uninfected cells to destroy themselves.

These findings collectively suggest that the timing of interferon treatment in COVID-19 needs to be carefully chosen. 

—Sean R. Hosein

REFERENCES:

  1. Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020 Aug;584(7821):463-469.
  2. King C, Sprent J. Dual nature of type I interferons in SARS-CoV-2-induced inflammation. Trends in Immunology. 2021; in press.
  3. Park A, Iwasaki A. Type I and type III interferons – induction, signaling, evasion, and application to combat COVID-19. Cell Host and Microbe. 2020 Jun 10;27(6):870-878.        
  4. McNab F, Mayer-Barber K, Sher A, et al. Type I interferons in infectious disease. Nature Reviews Immunology. 2015 Feb;15(2):87-103.
  5. Hoagland DA, Møller R, Uhl SA, et al. Leveraging the antiviral type I interferon system as a first line of defense against SARS-CoV-2 pathogenicity. Immunity. 2021 Jan 29:S1074-7613(21)00040-6.
  6. Van Eijk LE, Binkhorst M, Bourgonje AR, et al. COVID-19: immunopathology, pathophysiological mechanisms, and treatment options. Journal of Pathology. 2021; in press.
  7. Hadjadj J, Yatim N, Barnabei L, et al. Impaired type 1 interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020 Aug 7;369(6504):718-724.
  8. Bastard P, Rosen LV, Zhang Q, et al. Autoantibodies against type 1 interferons in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585.
  9. Zhang Q, Bastard P, Bolze A. Life-threatening COVID-19: Defective interferons unleash excessive inflammation. Med. 2020 Dec 18;1(1):14-20.
  10. Sallard E, Lescure FX, Yazdanpanah Y, et al. Type 1 interferons as a potential treatment against COVID-19. Antiviral Research. 2020 Jun;178:104791.
  11. Lazear HM, Schoggins JW, Diamond MS. Shared and distinct functions of type I and type III interferons. Immunity. 2019 Apr 16;50(4):907-923.
  12. Yuen CK, Lam JY, Wong WM, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerging Microbes and Infections. 2020 Dec;9(1):1418-1428.
  13. Durbin RK, Kotenko SV, Durbin JE. Interferon induction and function at the mucosal surface. Immunological Reviews. 2013 Sep;255(1):25-39.
  14. Briard B, Place DE, Kanneganti TD. DNA sensing in the innate immune response. Physiology. 2020 Mar 1;35(2):112-124.
  15. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nature Reviews Microbiology. 2009 Feb;7(2):99-109.
  16. Bedoui S, Herold MJ, Strasser A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nature Reviews Molecular Cell Biology. 2020 Nov;21(11):678-695.
  17. Calabrese LH, Winthrop K, Strand V, et al. Type I interferon, anti-interferon antibodies, and COVID-19. Lancet Rheumatology. 2021; in press.