Sunday, 15 December 2013 11:00

Turning Down Glucose Metabolism in Cells Slows Influenza Infection, Suggesting a New Strategy for Flu Therapy

Written by  ASCB Post Staff
Rate this item
(2 votes)

pressbook fluHigh glucose levels induce assembly of the V1 V0-ATPase
within cells— this correlates with higher viral infection.
Fever, ache, and the other miseries of influenza viral infection afflict 5−20 percent of the U.S. population each year. The "flu" is usually not life-threatening to the majority of its victims, but as the Spanish flu pandemic of 1918 showed, flu viruses can evolve into lethal agents and spread worldwide. The ability of flu viruses to change continually through mutation and genetic swaps is the reason that the Centers for Disease Control (CDC) reformulates the flu vaccine each year, hoping to block the types and subtypes of influenza viruses that they believe are most likely to be in circulation.

Yet to infect cells, the influenza virus is dependent upon the actions of the cell's own proteins, and so another strategy for slowing viral infection would be to target essential viral needs, for example, their dependence on cellular glucose. Which is what Amy Adamson and Hinissan Pascaline Kohio of the University of North Carolina, Greensboro, have done, showing that they could control influenza A infection in laboratory cultures of mammalian cells by altering glucose metabolism.

When the influenza virus initially infects a cell, and the virus is confined in an endocytic vesicle, the viral proteins HA and M2 use the acidic environment found inside the vesicle to fuse the viral lipid envelope with that of the vesicle, and then release the viral genome into the cytosol. The acidic pH that mediates these important viral events is established and maintained by the cell's vacuolar-type H+ ATPase (V-ATPase) proton pump. The researchers found that this dependence could be used to manipulate infection success.

First, Adamson and Kohio boosted glucose concentrations in the cell cultures, and influenza infection rate concomitantly increased. But treating the viral cells with a chemical that inhibits glucose metabolism significantly decreased viral replication in the lab cultures. Further, the researchers demonstrated that the infection could be restored to high levels simply by adding ATP, the major source of energy for cellular reactions, bypassing the need for glucose.

Looking closer, they discovered that higher levels of glucose promoted the assembly of the V-ATPase proton pump that drives the release of the influenza A genome into the cytoplasm, the internal watery environment of the cell. When Adamson and Kohio added the glucose inhibitor to the cell cultures, assembly of the molecular pump was suppressed. Viral infection, they concluded, was closely tied to the assembly of the V-ATPase pump, and this dependence could be used to manipulate infection success.

Specifically, they could suppress viral infection of cells by dismantling the V-ATPase through the lowering of glucose levels. In addition, they could inhibit infection by treating cells with chemical inhibitors of glycolysis, the initial pathway of glucose catabolism. Conversely, influenza viral infection of cells could be increased by giving cells more glucose than normal, the researchers report in the journal Virology.

The ease with which the researchers could dial viral infection down by controlling glucose levels and thus V-ATPase activity suggested a new strategy for throttling influenza viral infection. "Taken together, we propose that altering glucose metabolism may be a potential new approach to inhibit influenza viral infection," say Adamson and Kohio.