In The Food and Supplement Guide for the Coronavirus, I predicted that interferon contributes to the lung pathology of COVID-19 and could worsen the risk of severe disease and death. As a result, I screened all of the antiviral and immune support supplements I was considering for inclusion and recommended against anything that appeared to exert its antiviral activity primarily or substantially by promoting interferon. A new preprint* released today confirms my prediction.
My rationale had been as follows. SARS-CoV, the coronavirus that causes SARS, and MERS-CoV, the coronavirus that causes MERS, are both known to initially evade and suppress the initial interferon response, and to later lead to a dysregulated and excessive burst of interferon that damages the lungs. In humans with SARS, type 2 interferon plays an important role in the cytokine storm. Type 1 interferon damages the lungs and kills mice infected with SARS-CoV, the coronavirus that causes SARS, even though it prevents death in mice infected with flu or hepatitis viruses, and is broadly protective against viruses in general. Since SARS-CoV-2, the coronavirus that causes COVID-19, is 87% similar to to SARS-CoV, similar enough to be named after it, I believed the chances were high that interferon would turn out to be similarly harmful in COVID-19.
As a result, until more information comes in that may refute such a prediction, supplements that boost interferon strike me as potentially dangerous wild cards.
The new study released today confirmed that interferon plays similarly damaging roles in animal models of COVID-19.
They first tested the role of T cells, B cells, and interferon in mice that had only their own native ACE2. ACE2 is the entryway for the virus into cells, but mouse ACE2 is different enough from human ACE2 that the virus can't use it very effectively. The mice did develop infections, but with very little replication of the virus, very low viral loads, and very little damage to their tissues. Eliminating T cells and B cells made no difference. Eliminating the response to type 1 interferon increased viral loads and lung pathology somewhat, but didn't make the infection bad enough to consider it a useful model of human COVID-19.
These initial results showed three things:
The lack of human ACE2 strongly limits the level of viral infection that can be achieved in the mice.
In a low-level infection, the viral load is the main determinant of what little lung pathology there is.
In a low-level infection, interferon restricts the virus from replicating, but B cells and T cells do not.
Then they tested the role of interferons in Syrian hamsters. The hamster ACE2 is similar enough to the human ACE2 to allow a major infection, so hamsters proved to be a much better model.
They engineered the hamsters to lack proteins known as STAT2 and IL28R. Hamsters lacking STAT2 cannot respond to type 1 or type 3 interferon. Hamsters lacking IL28R lose their response only to type 3 interferon. The difference between hamsters without IL28R and normal hamsters shows the effect of type 3 interferon, and the difference between hamsters without STAT2 and hamsters without IL28R shows the effect of type 1 interferon.
The hamsters developed severe pneumonia that could be shown on CT scans, like human COVID-19.
Type 1 interferon, but not type 3, reduced the amount of virus in the lungs, the blood, the spleen, the liver, and the gastrointestinal tract.
Type 3 interferon made a modest contribution to the lung pathology, while type 1 interferon was the main contributor to lung pathology. In fact, removing the response to type 1 and type 3 interferons cut the lung pathology to only one-third the level that occurred in normal hamsters. Moreover, the CT scan-verified COVID-19-like pneumonia was completely absent in hamsters lacking the response to type 1 interferon.
These results are somewhat paradoxical, because they show that type 1 interferon restricts the replication of the virus and its spread to areas outside of the lung, yet is completely responsible for the pneumonia found on a CT scan and is the major driver of inflammation in the lung.
Until further data makes a clearer picture, I consider this confirmation that we should be very cautious with any supplements whose antiviral activities are primarily mediated through stimulation of interferon.
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.