COVID-19 Immunity: Too Little Can Be As Bad As Too Much
Precis: When two brothers fell critically ill with COVID-19 around the same time in March, their doctors were baffled. Both had been young and healthy, but within days they were unable to breathe on their own and one of them died. It suggested a genetic risk factor for severe COVID-19 disease. Two weeks later, a second pair of stricken brothers appeared in the Netherlands, and geneticists were called to investigate. They found a flaw in the brothers’ DNA that affected their resistance to the virus.
From the beginning of the COVID-19 pandemic, medical scientists have been baffled by the ferocity of the disease in some patients but not others. Especially baffling is the severity of the disease that sometimes even appears in healthy young people who have no preexisting high risk conditions. As we gain experience with this new pathogen and its disease, we are learning that there are several distinct factors related to viral pathology as well as to how the host responds to infection that lead to the disparate responses to CoV-2 infection.
Story: A pair of studies by the international COVID Human Genetic Effort research team that was recently published in the journal Science reveals novel aspects about what causes severe COVID-19 disease in certain patients. The studies report that about 15% of severe COVID-19 patients are deficient in a single cytokine called interferon. In other words, their severe disease is linked to an insufficient early immune response, which is the opposite of the over-reactive immune response called a “cytokine storm” that has been linked to severe disease in other patients.
“Cytokines” is the collective term for a wide range of small proteins secreted by a wide variety of immune cells, and even by non-immune body cells in response to infections. They play many roles in modulating the immune response, resisting infection, promoting inflammation, regulating temperature, blood pressure, and more. Some cytokines are important for mediating the earliest immune response we make to an infection, which is called “innate immunity.” This early response provides the first line of defense against a pathogen while a second, slower-developing response, or “adaptive immunity,” gears up to provide a more pathogen-specific, robust, and long-lasting protection.
Interferon (IFN) is one of the many cytokines that mediate the early innate immune response. There are several types of interferons that can interfere with viral replication, hence their name and role in innate immunity to viral infection.
In the first paper, investigators sequenced DNA from several genes known to affect early IFN responses. Genes from 659 critically ill patients who did not show signs of a cytokine storm, and from 534 patients with mild disease were compared. About 3.5% of the critically ill patients carried mutations in IFN regulatory genes and had almost undetectable IFN function. None of the control group showed any mutation in these genes or reduction in IFN levels or function. Notably, some of the IFN genetic defects also have been linked to life-threatening influenza pneumonia.
In the second study, scientists examined blood samples from 987 gravely ill patients and found that >10% of them had anti-IFN antibodies that neutralized their IFN activity leaving their cells unprotected against the early stages of CoV-2 infection and spread. None of the 663 patients with mild COVID-19 had the anti-interferon antibodies.
Intriguingly, 94% of the very ill patients with anti-interferon antibodies were men, which might partly explain why men are more susceptible to serious COVID-19 disease. However, this preponderance of male patients was surprising since women generally have a higher incidence of autoimmune disease. This observation suggests that there is an unknown X chromosome-linked recessive trait that influences the production of anti-IFN antibodies. Since women have two X chromosomes, both of them would have to carry the recessive gene in order to develop the antibodies while men, who only have one X chromosome, would only need the recessive gene on their lone X chromosome, giving them a greater probability of producing the anti-IFN antibodies.
Bottom line: It seems significant that none of these patients with deficient IFN responses had a history of other severe viral illnesses requiring hospitalization. This suggests that we are more reliant on this IFN response to protect ourselves against CoV-2 versus other viral infections.
Also, these studies have practical implications for treating COVID-19 patients. Recombinant interferon made in the laboratory has long been used to treat other viral diseases and could be part of an important therapeutic toolbox to treat COVID-19 patients who fail to produce sufficient IFN response to infection. Of course, this will not work in patients who have anti-IFN auto-antibodies that neutralize the activity of any IFN. But from years of experience dealing with auto-immune diseases, we do have an arsenal of other therapies that can mitigate these damaging auto-antibodies. Finally, recognition of these new high-risk subtypes, which can be identified via genetic and immunological screening, can identify individuals who should take extra precautions to avoid exposure to the virus, and those who should be at the head of the list to receive a vaccine when they are available.
In summary, both an over-exuberant immune response in the form of a cytokine storm, as well as an unenthusiastic immune response in the form of IFN deficiency can lead to severe COVID-19 disease. The optimal middling response is true for much of bioscience. You do not want to have a too high or too low blood pressure; ditto for body temperature; ditto for respiratory rate, blood pH, blood sugar, cholesterol, and so on.
Gotta love that happy middle.
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