Why does the COVID-19 virus make some people sicker than others? For years, scientists have looked to a critical piece of immune system machinery—known as the interferon pathway—for answers. There, when our cells sense an infection, they release a protein known as interferon, which warns other cells to fight the virus.

Studies show that when this signaling goes awry and leads the body to under or overreact, people are more likely to develop severe or long COVID. Glitches in this pathway have also been implicated in autoimmune diseases and cancer.

But little is known about what, precisely, drives these immunological misfires.

A new CU Boulder study, published Dec. 12 in the journal Cell, sheds light on the subject by identifying what the authors describe as an "immune system tuning dial," which originated as a bug in the genetic code tens of millions of years ago.

"We've discovered that there is an entire class of under-appreciated protein variants that can have an immense impact on our immune function," said senior author Ed Chuong, an assistant professor in the Department of Molecular, Cellular and Developmental Biology and the BioFrontiers Institute.

His lab demonstrated that one particular variant of a protein called IFNAR2 acts like a tuning dial to regulate interferon signaling.

"If we can manipulate this dial to turn the immune system up or down it could have broad therapeutic applications, from infection to autoimmune disorders to cancer."

How evolution turned a bug into a feature

Chuong studies transposons, bits of DNA that infiltrated primate cells as many as 70 million years ago and now make up more than half of the human genome.

Some transposons, known as endogenous retroviruses, got there via ancient viruses. When reawakened, these genetic parasites can help cancer survive and thrive. Others, like the ones explored in the new paper, emerged from the genome itself, like random bugs popping up in a computer program's source code.

"If you think of a gene as a sentence, a transposon is like a word that jumps into the sentence, making the instructions for the cell slightly different," explained first author Giulia Pasquesi, a postdoctoral researcher in Chuong's lab.

Cells normally suppress these bugs, ensuring only the correct version of the gene is spurred into action, so scientists have long viewed them as inert 'junk DNA."

Pasquesi set out to challenge this assumption, looking for gene variants formed by transposons that were actually important for human immune function.

When she analysed state-of-the-art genetic sequencing data from human tissues and cells, she found 125 instances across 99 genes.

A break in the antenna

Pasquesi and Chuong focused on a variant of interferon receptor 2 (IFNAR2)—a critical protein which acts like a cellular antenna for interferon, turning on other genes that fight off infection and cancer. They found that the new "short" variant could sense interferon, but it was missing parts required to transmit the signal.

Surprisingly, it was present in all cells, and often more abundant than the normal protein, suggesting it played an important role in immunity.

They followed up with laboratory studies using cells with different combinations of the two IFNAR2 varieties. They exposed them to immune challenges, including viral infections, finding that the short variant acted as a "decoy" that interferes with normal IFNAR2 signaling. When they removed the short variant from the genome, cells became much more sensitive to interferon, with stronger immune responses against viruses including SARS-CoV-2 and dengue virus.

The findings suggest that the balance between IFNAR2 variants acts as a "tuning dial" for controlling the strength of immune signaling, and this can vary from person to person. Individuals who express abnormally high levels of the variant might be more susceptible to severe infections, while people expressing low levels may have chronic inflammation, autoimmune issues like psoriasis or irritable bowel syndrome, or Long COVID.

"Different individuals are well known to exhibit differences in their immune responses, but the reasons why are still poorly understood. We've uncovered a new control dial that could be behind some of this variation," said Chuong.

The team has filed for a provisional patent and begun developing and testing compounds to therapeutically target the dial.

Bigger picture, they believe that the story of IFNAR2 is the tip of the iceberg, and many other immune functions may be regulated by these long-ignored genomic hitchhikers.

"Our findings suggest that looking into the dark corners of the genome is key to making new discoveries to improve human health," said Chuong.