Researchers have found a previously unknown mechanism by which the human immune system tries to battle the influenza A virus. The discovery by investigators from the University of Colorado Boulder and University of Texas at Austin is believed to offer new insights on how the virus often wins that battle, and could lead to new flu treatments, they said.

“We've solved a mystery, revealing a new aspect of our innate immune system and what flu has to do to get around it,” Nicholas Meyerson, Ph.D., a postdoctoral researcher in the BioFrontiers Institute and lead author of a “Nuclear TRIM25 Specifically Targets Influenza Virus Ribonucleoproteins to Block the Onset of RNA Chain Elongation,” a study published in the November 8 issue of the journal Cell Host & Microbe, said in a statement.

The findings could also shed new light on how the seasonal flu virus, which typically originates in birds, makes its way to humans. Influenza A kills 12,000 to 56,000 people in the U.S. annually, according to the U.S. Centers for Disease Control and Prevention. And last year’s influenza vaccine demonstrated only 20% to 30% effectiveness against a subtype of Influenza A virus, H3N2—with the potential for equally disappointing results this season—due to an adaptive mutation that affected egg-grown vaccines, but not vaccines produced in non-egg systems.

Results from the study may also undergird development of next-generation antivirals able to combat a broad spectrum of influenza strains, says Robert Krug, Ph.D., a professor at the University of Texas at Austin whose lab focuses on the molecular biology of influenza A and B viruses, and co-senior author of the study.

The study focused on the human protein TRIM25, recently discovered to play an important role in the human immune response to flu infection, and a protein called NS1 present in all strains of the influenza A virus and shown to bind TRIM25 to keep it from doing its job.

“We were basically trying to find out what TRIM25 was doing that flu did not want it to be doing and the role NS1 was playing in blocking that function,” Dr. Krug added.

Dr. Krug and colleagues found that TRIM25 acts earlier than previously believed, latching on to a critical and unique flu virus structure like a “molecular clamp” to keep the virus from replicating as soon as TRIM25 detects that structure. NS1 produced by the flu virus can block this function of TRIM25, enabling flu to circumvent the immune response and cause infection. The flu uses its NS1 protein to evade TRIM25's early flu-fighting response, the researchers said.

“Restriction Factor” Presence

The study also showed that TRIM25 is also a “restriction factor” protein present in the fastest-acting arm of the immune system before the spread of infection occurs. Previous research had suggested that TRIM25 fought off the flu virus by switching on the “interferon response” signaling pathway that enables cells through the body to fight off pathogens. Yet not all strains of influenza block this interferon signaling pathway, which led Dr. Meyerson to suspect another mechanism was at play in helping TRIM25 fight flu.

“Restriction factors lie in wait, and should a virus be detected in one of your cells, they have immediate destructive ability,” added co-senior author Sara Sawyer, Ph.D., an associate professor of molecular, cellular and developmental biology at the University of Colorado Boulder.

Researchers infected transgenic cell lines loaded with nonhuman primate versions of TRIM25 with the human influenza A virus. They found that the cells fought off the virus far better than human versions of the TRIM25 protein. “This told us that TRIM25 has the capacity to crush influenza, but that its human form was less active,” Meyerson said.

To learn how TRIM25 attacked influenza, the researchers combined purified TRIM25 with purified viral ribonucleoproteins (vRNPs)—eight-piece protein chains that house the influenza genome—and captured images using electron microscopy. They discovered that TRIM25 appeared to quickly recognize and inhibit the vRNPs in order to keep them from replicating inside the cell. This activity was inhibited by the NS1 protein in flu virus.

Researchers also found that TRIM25 is present in the cell nucleus, the same location in the cell where flu replication occurs. Until now, TRIM25 was believed to be present only in the cell cytoplasm.

Drs. Sawyer and Meyerson plan to follow up with further studies to explore how TRIM25 affects cross-species transmission of influenza, while Dr. Krug added that new treatments could be designed to block the NS1 protein produced by the flu virus, inhibiting its ability to evade the human immune system: “If you could somehow block NS1 from acting, you could block all strains of the virus.”

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