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Treating Influenza by Targeting Host

BEZ235, a cancer drug, appears to reverse influenza-induced metabolic changes in host cells, improving survival in infected mice.

By
Janelle Weaver, Contributor
Thu, 06/22/2017

B2D-June2017-influenza.10072.jpg

This 1973 colorized negative-stained transmission electron microscopic (TEM) image shows a number of influenza virions.

CDC/Dr. F. A. Murphy

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Influenza is a major public health problem that affects approximately one billion people worldwide each year, causing millions of cases of severe illness and hundreds of thousands of deaths around the world. According to the CDC, antiviral drugs like Tamiflu (oseltamivir) have been effective against the vast majority of influenza virus strains in recent flu seasons, but influenza is a fidgety bug. It undergoes constant genetic drift and is also capable of much more dramatic antigenic shift, recombining RNA segments with other flu viruses and possibly giving rise to a new, emergent strain.

The specter of shifting and drifting flu viruses informs the need for new treatment strategies, since emergent strains may acquire mutations that render them resistant to current antiviral drugs. One promising strategy to overcome the rise in viral resistance is to target host cells instead of the virus itself.

This could have a profound effect by reducing mortality and respiratory distress associated with influenza infections.

In a study published May 23 in Cell Reports, Heather Smallwood and her colleagues at the University of Tennessee Health Science Center and St. Jude Children’s Research Hospital in Memphis, Tennessee, identified therapeutic targets in host cells by examining how the influenza virus alters metabolic pathways in infected human respiratory cells. Moreover, they found that a drug called BEZ235, which is currently under investigation in clinical trials for the treatment of cancer, reverses these metabolic changes and improves survival in influenza-infected mice.

“If BEZ235 is used in combination with current antiviral therapies that attack the virus directly, we may be giving clinicians a powerful tool that could reduce disease duration and severity,” Smallwood said. “This could have a profound effect by reducing mortality and respiratory distress associated with influenza infections.”

As the flu virus buds from the host cell, it takes with it cellular resources such as lipids, proteins and nucleic acids, which need to be replaced by the cell. Based on this fact, Smallwood and her colleagues figured they should be able to find signs of virus-induced metabolic reprogramming in the host. Consistent with this idea, an analysis of positron emission tomography scans of 20 pediatric cancer patients diagnosed with respiratory viral infections revealed significant increases in glucose metabolism in the lungs.

To examine the underlying molecular mechanisms, the researchers next infected cells derived from the respiratory tract of two healthy young donors with the H1N1 influenza virus, otherwise known as swine flu. By quantifying the resulting changes in the host proteome, they found that influenza infection significantly alters in a variety of metabolic pathways.

these studies raise the possibility of clinical trials to test [BEZ235 treatment] efficacy against viral infections

Building on these findings, the authors designed a large-scale screen of 80 metabolic drugs to identify potential therapeutic compounds. One drug, BEZ235, stood out for its effectiveness at reducing viral concentrations, reversing influenza-induced metabolic changes in human respiratory cells infected with the H1N1 virus and increasing the survival of these cells. In mice infected with the H1N1 flu virus, BEZ235 treatment decreased viral concentrations in the lungs, improved respiratory function and significantly increased survival.

“Given that BEZ235 is a well-studied drug for cancer, these studies raise the possibility of clinical trials to test its efficacy against viral infections, influenza in particular,” said Peter Shepherd, who studies metabolic signaling pathways at the University of Auckland in New Zealand and was not involved in the new study. “The real work now lies in understanding how BEZ235 actually achieves its effects. While the broad effects the authors identify on metabolism may be part of the story, it is likely to be far more complex.”

Moving forward, Smallwood and her colleagues plan to test BEZ235 in combination with the antiviral drug Tamiflu, and determine the optimal treatment window. “We are also testing this drug on other respiratory viruses to determine if it can be used for other diseases that plague pediatric hospitals,” Smallwood said.