There might be a new kind of anti-viral medication coming to a pharmacy near you. An international research group led by the Hebrew University of Jerusalem has identified a set of genetic switches that controls a cell’s metabolic response to a virus. By using pharmaceuticals to inhibit or activate certain metabolic processes, the team was able to influence the success of the viral lifecycle within cells.
Viral infections have confounded scientists for decades. We understand what a virus looks like and that it works by hijacking a cell’s metabolic machinery to replicate itself. However, exactly how this interplay occurs is still somewhat of a mystery. The research group chose to study the Flaviviridae family of viruses, which includes Hepatitis C, Dengue, West Nile, Yellow Fever, and Zika viruses, because these viruses are considered to be expert metabolic engineers that have optimized the use of host metabolic processes to replicate and thrive.
In order to take a closer look into which metabolic processes viruses rely on to replicate themselves within a cell, the researchers turned to nuclear receptors, which are the genetic switches that regulate metabolism. Nuclear receptors are proteins that regulate the expression of various gene families to help cells sense and respond to changes in nutrition and adjust cell metabolism accordingly.
The team analyzed the metabolism of both infected and healthy liver cells. This gave them a comparison of what metabolic processes were being disturbed in the infected cells and allowed identification of the nuclear receptors involved in those processes. They were then able to block each receptor using targeted drugs and examine the effects on the virus.
"This is the first indication that our cells can block replication of Flaviviridae viruses like HCV and Zika by denying them from critical building blocks the viruses need to survive," said Prof. Yaakov Nahmias, Director of the Alexander Grass Center for Bioengineering at the Hebrew University of Jerusalem, who led the study. "Our results present a new approach to treat virus infection by targeting the genetic regulation of metabolic processes on which the virus rely."
The findings show that blocking glucose metabolism halted viral replication and increased apoptosis in infected cells, suggesting a direct viral reliance on glycolysis. However, blocking lipid metabolism actually increased viral replication. These results correlate to some of the effects of the HCV virus specifically, when it interferes with metabolic regulations and causes fatty liver disease and diabetes.
The study, published in Nature Chemical Biology
, provides evidence of a potential new type of anti-viral medication by targeting the nuclear receptors within infected cells that would be detrimental to the virus. Essentially, a cell’s own metabolic machinery can be used to resist a viral infection.
"This is a fascinating approach," said Prof. Oren Shibolet, head of the Department of Gastroenterology at Tel Aviv Sourasky Medical Center and Tel-Aviv University and a co-author of the study, "as the same methodology can be applied to study the metabolic regulation of liver cancer and other infections to possibly identify new therapeutic targets."
, Nature Chemical Biology
, Biology of Metabolism