For years, scientists have looked for answers in a critical piece of the immune system’s machinery, known as the interferon pathway. There, when our cells detect an infection, they release a protein known as interferon, which warns other cells to fight the virus.
Studies show that when this signaling fails and causes the body to under or overreact, people are more likely to develop severe or long COVID. Failures in this pathway have also been linked to autoimmune diseases and cancer.
But little is known about what exactly drives these immune failures.
A new study from CU Boulder, published December 12 in the journal Cellsheds light on the topic by identifying what the authors describe as an “immune system tuning dial,” which originated as an error in the genetic code tens of millions of years ago.
“We have discovered that there is a whole class of underappreciated protein variants that can have an immense impact on our immune function,” said senior author Ed Chuong, assistant professor in the Department of Molecular, Cellular and Developmental Biology and the BioFrontiers Institute.
His lab showed that a particular variant of a protein called IFNAR2 acts as a tuning dial to regulate interferon signaling.
“If we can manipulate this dial to increase or decrease the immune system, it could have broad therapeutic applications, from infections to autoimmune disorders and cancer.”
How evolution turned a bug into a feature
Chuong studies transposons, fragments of DNA that infiltrated primate cells about 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 those explored in the new paper, arose from the genome itself, like random errors that appear in the source code of a computer program.
“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 microbes, ensuring that only the correct version of the gene goes into action, which is why scientists have long viewed them as inert “junk DNA.”
Pasquesi set out to challenge this assumption, searching for genetic variants formed by transposons that were actually important for human immune function.
When he analyzed next-generation genetic sequencing data from human cells and tissues, he found 125 cases across 99 genes.
A break in the antenna.
Pasquesi and Chuong focused on a variant of interferon receptor 2 (IFNAR2), a critical protein that acts as a cellular antenna for interferon, activating other genes that fight infection and cancer. They discovered that the new “short” variant could detect interferon, but was missing the parts needed to transmit the signal.
Surprisingly, it was present in all cells and was often more abundant than the normal protein, suggesting that it played an important role in immunity.
They continued with laboratory studies using cells with different combinations of the two varieties of IFNAR2. They exposed them to immunological challenges, including viral infections, and found that the short variant acted as a “decoy” that interferes with normal IFNAR2 signaling. When they removed the short variant from the genome, the cells became much more sensitive to interferon, with stronger immune responses against viruses such as SARS-CoV-2 and the dengue virus.
The findings suggest that the balance between IFNAR2 variants acts as a “tuning dial” to control the strength of immune signaling, and this may vary from person to person. People who express abnormally high levels of the variant may be more susceptible to serious infections, while people who express low levels may have chronic inflammation, autoimmune problems such as psoriasis or irritable bowel syndrome, or long COVID.
“It is well known that different individuals exhibit differences in their immune responses, but the reasons are not yet well understood. We have discovered a new control dial that could be behind some of these variations,” Chuong said.
The team applied for a provisional patent and began developing and testing compounds to therapeutically target the dial.
More broadly, they believe the IFNAR2 story is the tip of the iceberg, and many other immune functions may be regulated by these long-overlooked genomic hitchhikers.
“Our findings suggest that looking into the dark corners of the genome is key to making new discoveries that improve human health,” Chuong said.