Researchers have identified a variant of a protein that acts as a mechanism to control the body’s innate immune response. This discovery could pave the way for new treatments for Long COVID, autoimmune diseases, and more.
What causes the COVID-19 virus to affect some individuals more severely than others?
For many years, scientists have been examining a vital component of the immune system called the interferon pathway to find answers. When our cells detect an infection, they produce a protein called interferon that alerts neighboring cells to help combat the virus.
Research indicates that when this signaling process malfunctions, leading the body to either react too little or too much, individuals are more at risk of developing severe symptoms or Long COVID. Disruptions in this pathway have also been linked to autoimmune diseases and cancers.
However, the specific factors that contribute to these immune system failures are not well understood.
A recent study from CU Boulder, published on December 12 in the journal Cell, sheds light on this topic by identifying what the authors refer to as an “immune system tuning dial,” which arose from a genetic mutation millions of years ago.
“We’ve uncovered a whole class of overlooked protein variants that can significantly influence our immune system,” stated Ed Chuong, the senior author and an assistant professor in the Department of Molecular, Cellular, and Developmental Biology and the BioFrontiers Institute.
His research team found that a specific variant of the protein called IFNAR2 serves as a tuning mechanism for regulating interferon signaling.
“If we can adjust this mechanism to modulate the immune response, it could lead to broad therapeutic possibilities, ranging from infections to autoimmune diseases and cancer,” he added.
How Evolution Turned a Flaw into a Benefit
Chuong studies transposons, segments of DNA that inserted themselves into primate cells up to 70 million years ago and now account for over half of the human genome.
Some transposons, classified as endogenous retroviruses, entered through ancient viral infections. When reactivated, these genetic elements can assist in cancer survival and proliferation. Others, like the ones discussed in this new study, have originated directly from the genome, similar to unexpected bugs appearing in a computer program’s code.
“Consider a gene as a sentence; a transposon is akin to a word that hops into the sentence, altering the instructions for the cell slightly,” explained Giulia Pasquesi, the first author and a postdoctoral researcher in Chuong’s lab.
Typically, cells suppress these genetic intrusions, ensuring that only the correct gene version is activated, which is why scientists have long regarded them as ‘junk DNA’.
Pasquesi aimed to challenge this perception by investigating gene variants created by transposons that could actually play a significant role in human immunity.
After analyzing advanced genetic sequencing data from human tissues and cells, she discovered 125 cases across 99 different genes.
A Disruption in the Signal
Focusing on a variant of the interferon receptor 2 (IFNAR2)—a key protein that acts as a cellular sensor for interferon, activating genes fighting off infections and cancers—Pasquesi and Chuong found that this new “short” variant was capable of detecting interferon but lacked elements needed to relay the signal effectively.
Surprisingly, this short variant was found in all cells and was often more prevalent than the normal form, indicating its potential significance in immune response.
Through laboratory experiments, they tested cells with different combinations of the two IFNAR2 variants under various immune challenges, including viral infections. They discovered that the short variant acted as a “decoy,” disrupting normal IFNAR2 signaling. Removing the short variant resulted in cells becoming more responsive to interferon, showing heightened immune reactions against viruses like SARS-CoV-2 and dengue virus.
The results suggest that the interplay between IFNAR2 variants functions as a “tuning dial” that modulates the intensity of immune signaling, which can differ significantly among individuals. Those expressing higher levels of this variant may be more prone to severe infections, while those with lower levels might experience chronic inflammation, autoimmune conditions such as psoriasis or irritable bowel syndrome, or Long COVID.
The research team has filed for a provisional patent and is currently working on developing compounds to target this regulatory mechanism therapeutically.
In the larger context, they believe the discovery related to IFNAR2 is just the beginning and many more immune functions may be influenced by these previously neglected genomic elements.
“Our research implies that exploring the overlooked areas of the genome is crucial for making new advancements in human health,” concluded Chuong.
