Researchers have found critical details about how flu bugs dodge the immune system and trigger disease.
The study shows that influenza A viruses use a sophisticated technique to disable the cell’s early alarm system before it starts producing key antiviral warriors called interferons.
“We think this is the most critical mechanism that flu uses to block interferon and cause disease,” said lead author Michaela Gack, HMS instructor in microbiology and molecular genetics at the New England Primate Research Center.
Gack and colleagues focused on the influenza A virus, the most common and virulent flu type that includes human and animal strains such as the H1N1 (swine) flu. The study was published in Cell Host and Microbe on May 21.
“This is a very interesting paper,” said John Hiscott of McGill University, a virologist who was not involved in the study. Understanding how these viruses are interfering with the immune response and the sensing of incoming infections is really critical.”
The new study will not deliver a quick remedy for the H1N1 flu epidemic, but researchers said that it may lead to more effective antiviral drugs to combat multiple flu strains in the future.
Annual vaccines are still the most effective way to prevent flu infection, but producing them is a demanding and time-consuming process. The other alternative is using antivirals, which grant protection against multiple strains. However, many viruses are growing resistant to them.
One approach toward better treatments is finding what is crucial for flu’s survival and targeting it with a new drug. That is part of the job of Adolfo García-Sastre, a renowned flu expert at Mount Sinai School of Medicine in New York. Ten years ago, he found a possible candidate known as NS1. This flu protein seemed to block the innate immune system, the first line of immune defense, which sparks interferon production when pathogens are detected. But how exactly NS1 blocks the immune response has remained a puzzle.
Two years ago, Gack shed some light on the question while pursuing her PhD in the lab of HMS professor of microbiology Jae Jung. She discovered that a protein, TRIM25, is essential to jump-start the chain reaction leading to the innate response (see Focus, May 18, 2007). Now, Gack, García-Sastre and colleagues have discovered that influenza A shuts down the immune response before it even gets started.
TRIM25 is key to keeping antiviral sensors active inside cells. It attaches a chain of ubiquitin proteins to an intracellular sensor known as RIG-I. This chain enables the sensor to call for interferons whenever it spots a virus. But Gack and colleagues discovered that the flu’s NS1 protein binds to TRIM25 and blocks its action. Without the aid of TRIM25, the RIG-I sensor is muted, and the virus can continue its harmful progression unnoticed.
“The first thing I thought when I saw this was, wow!” said García-Sastre, whose lab has been seeking to clarify this mechanism for more than 10 years. Other TRIM family proteins are well-known fighters against HIV and other viruses, but this is the first account of a virus targeting TRIM25 to shut down interferon production, the researchers said.
“It’s a pretty smart strategy,” said Hiscott. Viruses have been investigating the host immune response for eons and this mechanism exemplifies the ingenious strategies they have developed.
The team showed influenza A viruses have been using this tactic for a long time. Up to eight human and animal strains, including the one from 1918 that killed about 50 million people around the world and the avian H5N1 strain, produce NS1 to interact with TRIM25.
The mechanism also seems to be essential for flu’s multiplication and virulence. When the team infected human lung cells with a mutant virus that could not block TRIM25, they observed a dramatic reduction of virus replication compared to cells exposed to regular influenza A. Mice injected with the regular strain died within six days, but none of those receiving the mutant version did.
“The flu virus has to target TRIM25 if it wants to replicate and cause disease,” said Gack. Influenza A will typically have to breach several other layers of immunity, but researchers think this finding can help them stop the bug at an early stage of infection.
García-Sastre said that the team will now begin looking for molecules that could block the viral protein and grant immunity against multiple strains of influenza A. An additional approach is developing vaccines with a virus whose NS1 activity is attenuated. “We expect very much that it will work,” said Gack.
Students may contact Michaela Gack at michaela_gack@hms.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: NIH, Genome Network Project from the MEXT and the exchange program between Harvard Medical School and the Friedrich-Alexander University Erlangen-Nuremberg.
