Targeting the flu

Pediatric researchers with Le Bonheur Children’s Hospital have found a promising new approach for treating the flu by targeting cell metabolism rather than the virus.

The scientists have discovered that administering a drug designed to decrease tumor volume also works to dial down viral production and has dramatically increased survival of flu-infected mice. Influenza is a leading cause of hospitalization and death in the United States and worldwide. Children, the elderly and the immune-compromised are at a greater risk for mortality due to complications from the virus, which turns infected lung cells into replication factories.

The  findings from researchers at Le Bonheur’s Children’s Foundation Research Institute and University of Tennessee Health Science Center recently appeared in the journal, Cell Reports.

“The flu infection is as ubiquitous as it is complex, but genetically the virus is very simple” said Heather Smallwood, PhD, lead author of the study and assistant professor at UTHSC. “What we’re hoping is that by slowing down the infected cell’s metabolism we can hold the virus at bay, allowing the natural immune system to come into play.”

Currently, a flu shot is the best protection against the virus, but the flu’s adaptability combined with the unpredictability of strain prevalence year to year can cause headaches for clinicians each season. And when it comes to anti-viral medications such as Tamiflu, a patient must be seen shortly after experiencing symptoms to receive any benefit. Drug resistance also poses an issue for anti-viral treatments.

Taking a new approach, researchers first showed that flu infection changes the metabolism of human lung epithelial cells, the prime location for viral multiplication. The flu and other respiratory viruses radically increased the cells’ dependence on glucose and glutamine, which are the raw materials of viral production. Smallwood, who began this work as a post-doctoral fellow at St. Jude Children’s Research Hospital, reviewed PET scans of 20 pediatric cancer patients and found increased glucose metabolism in the lungs of patients with respiratory infections compared to those without infections.

Working with a platform designed to target tumor cells, the researchers screened 80 small molecules and drugs and identified several, including the drug BEZ235 (Dactolisib), which blocked viral replication in human lung epithelial cells.

Researchers showed that BEZ235 reversed infection-induced intracellular metabolic changes and significantly reduced content of a pandemic strain of the virus in the lungs while easing respiratory symptoms. Survival outcomes in mice increased from approximately 15 percent to 60 percent.

“In spite of the lack of flu proteins directly involved in metabolism we found it profoundly changes host metabolism,” said Smallwood. “Host response and the virus are both fueled by high metabolic rates; we believe this is a fundamental necessity for all viruses that require host machinery for molecular synthesis. This is very exciting as it opens up the opportunity for us to develop new drugs based on this one, as well as optimize the efficacy of the existing drug.”