Researchers have uncovered new functions of a protein previously recognized for its role in defending against severe influenza infections. Among these roles is its ability to increase the minimum viral load necessary to trigger illness.
Researchers have uncovered new functions of a protein previously recognized for its role in defending against severe influenza infections. Among these roles is its ability to increase the minimum viral load necessary to trigger illness.
The study revealed that this protein also plays a protective role by preventing unfamiliar viruses from evolving rapidly after they infect a new host. This means that if this protein is lacking during an immune response, animal viruses that cross over to humans could adapt swiftly to human hosts.
Findings from scientists at The Ohio State University suggest that individuals lacking this protein, known as IFITM3, could face significant risks, particularly if an avian or swine flu strain starts spreading among humans and causes a major outbreak.
IFITM3 deficiency is relatively common: Approximately 20% of individuals of Chinese descent and 4% of those of European ancestry possess genetic mutations that limit their immune system’s ability to produce this protein.
“A deficiency in IFITM3 makes it easier for a low viral dose to lead to infection,” explained Jacob Yount, the study’s lead author and a professor of microbial infection and immunity at Ohio State’s College of Medicine.
The Centers for Disease Control and Prevention is currently monitoring the H5N1 avian flu, which is prevalent in wild birds and has been causing outbreaks in poultry and dairy cows in the U.S. So far, there have been 45 reported human cases.
“It’s these emerging viruses that we’ve never encountered before that make IFITM3 particularly crucial,” Yount emphasized. “This study supports the idea that not only can a person with an IFITM3 deficiency experience a more severe infection, but they are also at a higher risk of infection and may facilitate the virus’s adaptation.”
The research findings were published on October 30 in Nature Communications.
IFITM3 (pronounced “I-fit-M-3,” short for interferon-induced transmembrane protein 3) is essential for the innate immune system’s ability to eliminate viruses. It is produced in high amounts when the flu virus is present and mitigates the infection’s severity by trapping the virus and preventing it from replicating.
Yount has researched flu viruses and this protein for several years, creating a mouse model devoid of the IFITM3 gene, which makes these mice highly susceptible to influenza.
In this latest study, his team aimed to expand the understanding of IFITM3 concerning risks associated with infections crossing species barriers—particularly the transfer of avian or swine flu to humans, which has caused pandemics throughout history.
The researchers examined how infectious two strains of avian flu, including H5N1, were at various viral particle levels in both IFITM3-deficient mice and typical mice. At doses of approximately 10 and 50 viral particles, all mice showed detectable viral loads. However, in the mice lacking IFITM3, just a single viral particle was sufficient to cause infection and inflammation, while the normal mice remained uninfected.
“While IFITM3 has been recognized for preventing severe infections, this study highlights its influence on the amount of virus required for initial infection,” Yount stated. “This discovery is one of the most significant insights to come from my lab.”
Further experiments using cultures of human lung lining and immune cells indicated that cells where the IFITM3 gene was silenced had a significantly increased susceptibility to 11 avian, three swine, and two human flu viruses.
“Every tested virus showed a higher infection rate when IFITM3 was deficient. This reinforces the notion that IFITM3 is crucial in inhibiting influenza infections universally,” Yount noted.
The team conducted laboratory experiments simulating repeated transmission of a human-origin virus in mice to assess the protein’s role in the mutations that facilitate interspecies adaptation. Results showed that flu viruses replicated faster and caused more severe inflammation in IFITM3-deficient mice compared to those with normal levels of the protein.
“Thus, a virus from another species adapts more quickly in the absence of IFITM3. This serves as proof of principle since we are examining this in a mouse model,” Yount explained.
“In summary, our study demonstrates that IFITM3 is broadly significant in defending against zoonotic viruses across various influenza strains capable of infecting humans. Our findings suggest that individuals genetically deficient in IFITM3 are particularly at risk for new viruses crossing from animals to humans.”
Given this information, it is important to consider people with IFITM3 deficiency in pandemic preparedness strategies, Yount suggested.
This research was supported by grants from the National Institutes of Health.
Co-authors include Parker Denz, Samuel Speaks, Adam Kenney, Adrian Eddy, Jonathan Papa, Jack Roettger, Sydney Scace, Emily Hemann, Adriana Forero, and Andrew Bowman from Ohio State, as well as Adam Rubrum and Richard Webby from St. Jude Children’s Research Hospital.
