Viral infection — from the Hepatitis C virus that affects three percent of the global population and recent outbreaks of the Zika and Ebola viruses — is one of the leading medical challenges of the 21st century.
New research led by the Hebrew University of Jerusalem says there may be a new way to resist virus infections: by targeting the genetic regulation of metabolic processes on which viruses rely to replicate.
Participating in the research were The Hebrew University of Jerusalem, Harvard Medical School, Broad Institute of MIT and Harvard, Tel Aviv University, University Duisburg-Essen, and the University of Düsseldorf.
Viruses are parasites that lack the basic metabolic machinery needed to replicate. To get around this problem, they hijack the metabolic machinery of their hosts in order to complete their life cycle and propagate. However, scientists have never had a good understanding of the metabolic interplay between viruses and the organisms they infect.
In the new research, which appears in the journal Nature Chemical Biology, the international team said it systematically identified a number of genetic switches that control the metabolic response to the Hepatitis C virus (HCV) infection.
By carefully selecting drugs that target these genetic switches, the researchers were able to show how these genes control metabolic processes, such as glucose and lipid metabolism, and to establish how these processes affect the virus life cycle. Surprisingly, while some metabolic processes were beneficial for the virus, for example by providing it with building blocks for its genetic material allowing it to replicate faster, other metabolic processes were surprisingly anti-viral, disturbing the virus’s life cycle.
“This is the first indication that our cells can block replication of Flaviviridae viruses like HCV and Zika by denying them 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 treating virus infection by targeting the genetic regulation of metabolic processes on which the virus rely.”
Metabolism is a complex phenomenon regulated primarily by genetic switches called nuclear receptors. Nuclear receptors are a family of proteins found within cells that are activated by metabolites such as fatty acids or glucose, acting as sensors that allow cells to sense and respond to changes in nutrition — like meals — by regulating the activation of hundreds of genes.
Viruses such as HCV can interfere with this metabolic regulation. When this happens, it results in fatty liver disease and diabetes in infected patients.
To find the mechanism by which viruses such as HCV can interfere with metabolic regulation, the researchers used a new laboratory model of human liver cells developed by Prof. Nahmias. By mapping out the metabolism of both infected liver cells and normal liver cells, they were able to focus on disturbed metabolic processes and identify the nuclear receptors responsible for their dysregulation.
Once the researchers identified the genetic switches controlling the disturbed metabolic processes, they blocked each nuclear receptor using pharmaceuticals, and studied the effects of this inhibition on the virus. While blocking glucose metabolism was detrimental to the virus, blocking lipid metabolism had the reverse effect, actually increasing HCV replication.
The authors pointed out that the Flaviviridae family of viruses, which includes Hepatitis C, dengue, West Nile, yellow fever, and Zika viruses, were previously considered to be expert metabolic engineers that optimized the hijacking of host metabolic machinery to create more viruses.
“It was quite surprising to see that human liver cells could use metabolic processes to resist viral infection,” said Prof. Jörg Timm, a co-author from the Institute of Virology at the University of Düsseldorf. “It went against our common understanding of viruses as expert metabolic engineers, suggesting new avenues to target virus infection.”