Investigators Uncover How Flu Virus Eludes the Body's Defenses

Researchers at the University of Southern California (USC) identified a molecular mechanism that allows the influenza virus to evade the body's immune response system. The virus’ nonstructural protein 1 (NS1) targets a particular ubiquitin ligase to hide from the host viral RNA sensor.

The influenza A virus has evolved the NS1 protein into its genome to escape the immune system, but the precise process it uses has been unclear. “We now know that the influenza virus escapes recognition via the interaction of NS1 with TRIM25, which inhibits the body's immune response,” explains Jae Jung, Ph.D., professor and chair of the department of molecular microbiology and immunology at the Keck School of Medicine of USC.

Dr. Jung also is the principal investigator of the study called “Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host Viral RNA Sensor RIG-I,” published in the May 21 issue of Cell Host & Microbe. The study was conducted along with scientists from Mount Sinai Medical School and Harvard Medical School.

When a virus’ RNA enters the intracellular fluid, a receptor known as retinoic-acid-inducible gene I (RIG-I) usually detects it and triggers a response that limits virus replication and calls the body's defenses into action. Then, a protein called TRIM25 helps RIG-I transmit a signal, which ultimately floods the cell and surrounding tissue with antiviral interferons.

Using animal models, the USC team found that the influenza A virus NS1 attacks TRIM25, inhibiting its ability to assist RIG-I. A flu virus carrying an NS1 mutant defective for this activity loses its virulence in animal models, according to Dr. Jung.