Cellular immune problems are why young people can die from COVID-19

One of the most disturbing problems in COVID-19 medicine care has been that a few young people have become extremely ill with this infection. While these cases are rare, they unnerve physicians because the patients have not had the chronic Illnesses that predispose most people to serious COVID-19 infections. Many of us have thought that these individuals have some type of occult genetic problem that prevents their immune system from protecting them from the virus. There is now data to back that hypothesis. 

A recent paper published in the Journal of the American Medical Association (JAMA) reports on four young men from two families who were hospitalized in the Netherlands with COVID-19. These two sets of brothers had severe COVID-19 infections, and the presumption was that having more than one family member with severe disease would indicate a genetic problem. One of the individuals died from his infection.

All four of the individuals were screened for genetic abnormalities by analyzing the entire coding sequence for every protein in their body (whole exome sequencing). The ability to do this analysis, relatively inexpensively and rapidly, has only recently been accomplished. Screening all the proteins of the body provides a quick method of determining if there is a single abnormality in immunity that might be associated with severe COVID-19 infection. Screening other family members, especially with the same illness, indicates if this defect is shared, providing substantiation of the likelihood it is behind the illness; in this case severe COVID-19 infection. 

Remarkably, all four individuals had defects in a single protein, the X-chromosomal toll-like receptor sever (TLR7) protein. This is an innate immune signaling system that recognizes single stranded RNA (as is found in the COVID-19 virus) and stimulates the body’s cellular immunity, causing lymphocytes to produce anti-viral compounds like interferons. Each family had a different genetic abnormality, but in both families, it caused this gene not to function. Because this gene was on the X protein, each male has only one copy (only one X chromosome) so if that one gene is defective the abnormality impacts all immune function.

This defect significantly decreased the messenger RNA (mRNA) and therefore the amounts of several signaling proteins including IRF7, IFNB1, and ISG15. The end result was decreases in production of interferon gamma (IFN-γ), an essential anti-viral protein. Family members that did not get ill with COVID-19 uniformly had normal copies of the defective gene.

There are several take home points from this finding. The first is cellular immunity is crucial to protection against COVID-19. This is important in understanding, and vaccines must generate this type of immunity to protect against COVID-19 infection. It is also interesting that different defects in this specific pathway caused severe disease given it specifically responds to single stranded RNA viruses like COVID-19. Also, since many immune genes are on the X chromosome, and males only get one copy, this may be why men are more likely to get sick and die from COVID-19.

The talk about antibody and immunity to this virus also needs to be tempered since another recent publication showed that people that don’t make significant antibodies can survive COVID-19. Because of this, evaluations of vaccines and herd immunity to COVID-19 should be based on cellular immunity and not on antibody to the virus.

Finally, as we identify these kinds of abnormalities we can start screening young people (especially males) with severe COVID-19 for defective genes and treat them by giving IFN-γ as a drug. This could potentially save lives!