Investigational therapy reduces flu production in influenza-infected mice by targeting cell metabolism.
A drug initially developed for cancer, known as BEZ235 may aid in curing those infected with influenza. Scientists at St. Jude Children’s Research Hospital have discovered a link between the investigational therapy and its ability to decrease viral production of the flu virus within the lungs. The influenza virus effectively spreads by “hijacking” the lung cells, which are used to create copies of the virus and wreck havoc on the body. However, when cell metabolism is targeted via the BEZ235 treatment, mice infected with the flu virus experienced increased survival rates.
The lung’s epithelial cells are the main location for the replication of the influenza virus. Once in the lungs, the virus proceeds to alter the metabolism of the cells, making them more heavily dependent on glucose and glutamine, which is — not so coincidentally —needed for the virus to produce and thrive. PET scans taken of 20 immune-compromised pediatric cancer patients infected with the flu and other respiratory infections demonstrated a dramatically increased glucose metabolism when compared to those who were not infected.
Paul Thomas, Ph.D., an associate member of the St. Jude Department of Immunology explained, "Previously, little was known about how flu infection changed the metabolism of lung epithelial cells; but based on early evidence in this study we suspected metabolism was an Achilles heel of the virus,"
BEZ235 inhibits the PI3K and mTOR metabolic pathways, which promote rapid cell division — this unchecked cell division is a staple of cancer. BEZ235 is currently in clinical trials for the treatment of solid tumors. When tested on the flu virus, BEZ235 brought PI3K and mTOR pathways, which are also active in flu infection, down to pre-infection levels. Viral replication was greatly reduced by changing the cell metabolism and making glucose and glutamine less available, thus cutting off the source needed for the virus to replicate. The drug did not fully block the infection from entering the lungs, however.
"This approach works by reducing viral replication, which suggests there might be a treatment window that lasts several days in which drugs could be used to reduce the infection and risk of complications," commented Thomas.
"By focusing on changing how infected cells respond to the resulting metabolic stress rather than targeting a component of the virus itself, there is less risk that the virus will become resistant to the drugs," he added.
This new way of looking at respiratory viruses marks a breakthrough, especially as the flu vaccine must be constantly altered to keep up with new strains of the virus, and is always be a step ahead. Additional research is planned in part to determine if targeting metabolism might also be effective against other respiratory viruses, including emerging respiratory viruses or others like Respiratory Syncytial Virus (RSV), which causes life-threatening infections in infants.