Does life-threatening COVID-19 have anything to do with your genes?

by Janice Nigro

Early in the SARS-CoV-2 pandemic, a non-scientist, the husband of a cousin of mine, asked, “Does  life-threatening COVID-19 have anything to do with your genes?” At the time, he saw Italians and men dominating the list of persons worldwide succumbing to the pathogen. I didn’t know, and truth be told, as a molecular biologist and cancer researcher, I was embarrassed that I hadn’t even thought of asking that question yet.

Although I didn’t think to ask the question, differences, known as variants or mutations, in specific genes are already known to disrupt the immune system. Rare genetic syndromes exist, such as the famous “boy in the bubble”, rendering the immune system incapable of mounting an effective response against many different, but common pathogens. Variants in other genes are more subtle and may become evident only with certain pathogens. Some of these genes have turned out to be in networks involving interferon, a key protein stimulating the first wave of immune defense. 

What does interferon do?

SARS-CoV-2, as for any virus, persists if it enters human cells where only there can it make copies of itself. It gains entry through an initial interaction between specific proteins on the surfaces of the virus and the human cell. It’s a little bit like having the right password to gain access to the computer. The interaction between the Spike protein, which decorates the virus like solar rays, and the angiotensin-converting enzyme 2 (ACE2) receptor on a human cell allows the virus access to the cell machinery it desperately needs to reproduce itself. 

Once in, the virus sets off an alarm like a bungling intruder. The alarm is tipped off by the foreign viral RNA and engages a specific network to defend against reproduction of the virus. If the alarm works, cells produce interferon. As its name implies, interferon interferes with viral replication. It does so by disrupting two processes fundamental for viral reproduction: copying the viral RNA genome and the translation of it into proteins. 

Without interferon, viruses multiply in an uncontrolled fashion, possibly killing, in the case of SARS-CoV-2, lung cells. These dying cells call in immune cell types which can cause further damage to lung tissue rather than clear the infection. So the possible consequences of a poor early immune response to SARS-CoV-2 is life-threatening COVID-19. 

If this first step in the immune response hinges on the production of interferon and its impact on setting up an initial viral defense, are genes involved in this network compromised in some people? 

Do gene mutations affect your immune response to SARS-CoV-2?

To get an answer requires a bit more digging than watching the numbers of specific demographic groups spin freakishly out of control on the Worldometers website. With today’s sensitive high-throughput technology, genomic sequencing, it’s possible, almost easy to take a peek into the 30,000 genes of any single person in less than a couple of weeks. 

In a clever study from the Netherlands, scientists increased their odds of finding genetic variants affecting COVID-19 outcome to just four out of 11,430 people hospitalized for the disease. They looked first in a demographic where severe complications from SARS-CoV-2 are rare – in young patients without preexisting conditions. Then they asked whether any were related.

Among the 399 hospitalized patients under the age of 35 (at the time of the study) were two sets of brothers who had been previously healthy but landed in the ICU with COVID-19. 

Sequencing of the DNA (the genomes) of these four patients and their closest family members revealed differences in a candidate gene called toll-like receptor 7 (TLR7). It’s a gene conserved from flies to humans, and it just happens to turn on interferon in response to pathogens.

TLR7 is missing a portion of the gene in one family while a single nucleotide changes the protein in the other. These mutations in TLR7 also help to explain why more men might suffer severe complications from SARS-CoV-2 – the gene is located on the X chromosome.

Every gene in humans has two copies except in the case of those on the sex chromosomes. While biological women have two X chromosomes, biological men have only one X chromosome which means only one copy of TLR7. In these brother pairs, the only copy present is a deficient one, rendering the young men vulnerable to SARS-CoV-2 and providing one biological possibility for the differences in COVID-19 response between men and women.

Genetic changes in humans, as in this case, are typically discovered because of a health issue. Nonetheless, their existence helps in the understanding what such genes do. TLR7 was presumed to stimulate the production of interferon in certain cell types, such as those in the lung. COVID-19 has shown that the natural stimulant might be viral RNA.

Are there other genes? 

There’s more than one way to turn on interferon. Not all viruses stimulate the same gene network to increase interferon. And some genetic changes might affect the activity rather than the amount of interferon. So while TLR7 is one example of a gene mutation associated with potentially fatal COVID-19, mutations in other genes might possibly exist. SARS-CoV-2 is a new disease in humans, but mutations in a related gene called toll-like receptor 3 (TLR3) are also responsible for life-threatening illness in response to other pathogens. 

The hunt for other genes began in a search through the sequences of 13 different genes related to immune response in 659 people of diverse ancestries, including those from Asia, Europe, Latin America, and the Middle East, who suffered or died from COVID-19. Of the 13 genes examined, 23 of 659 patients had a mutation in one of them.

That’s only 3.5% of unrelated patients with severe COVID-19. Yet one of these variants was previously found in a person who suffered a life-threatening bout of pneumonia. 

Biological men make antibodies against interferon

Linkage to the X chromosome came up in a study examining another phenomenon known to contribute to the severity of some infectious diseases. It turns out that your own body might make antibodies against interferon. These antibodies bind to your own interferon effectively blocking its activity. 

So investigators worldwide looked for antibodies against interferon in patients hospitalized for life threatening COVID-19. Out of 987 patients, 101 had autoantibodies against interferon, while none were present in 663 patients who had an asymptomatic or a mild case of COVID-19. These interferon autoantibodies are thought to be a cause rather than a consequence of the disease as they were detected in plasma from patients before infection. 

The most interesting result of this study is that patients with these autoantibodies were predominantly male – 95 out of 101! Is the phenomenon associated with the number of X chromosomes present? Another clue is that one of the seven women with autoantibodies and life-threatening disease had an X-linked disorder, incontientia pigmenti, in which only a single X chromosome is active. 

Therapeutic implications

Even though genetics might influence COVID-19 outcome, especially in outliers in some demographics such as young men, it’s still rare. And less than half of a percent of the general population was positive for antibodies against interferon. Neither phenomenon accounts for the majority of persons with life-threatening disease, many of whom have underlying comorbidities. 

Both findings, however, emphasize the importance of the first line of immune defense – your innate immunity – against SARS-CoV-2 in human cells. They also highlight possible strategies for the treatment of hospitalized COVID-19 patients.

 

Until next time…Stay safe!

 

©Janice Marie Nigro/janikiInk.com

Looking for a scientific editor or writer? Contact Janice Nigro at Janice Nigro Ink. I have published in Cell, Science, and Nature, and articles I have edited have appeared in Cancer Research, Clinical Cancer Research, PLoSONE, the Journal of Surgical Oncology, and Oncotarget.