Researchers at the Morgridge Institute for Research believe they have identified a weak spot in the replication process of positive-strand RNA viruses, which could yield treatment for viral infections such as Zika, Polio, Chikungunya, Hepatitis C and even common cold viruses.
RNA viruses bind to mitochondria. credit: Mopic/ Shutterstock.com
The team was led by Paul Ahlquist, Professor of oncology and molecular virology at the University of Wisconsin-Madison, and the study appeared late last week in the journal Science Advances.
According to Masaki Nishikiori, from the Morgridge Institute virology group, these RNA viruses work by penetrating the walls of the intracellular organelles to which they attach. These viruses bind to mitochondria and endoplasmic reticulum while processing their gene replication to facilitate multiplication.
Earlier it was believed that genome replication took place on one side of the membrane alone. This new finding could prove that if the viruses were unable to bore holes in the walls of the organelles, they may not be able to replicate and cause the infection to spread.
Positive-strand RNA viruses include common cold virus and are one of the largest family of viruses. Developing treatment to prevent replication of these viruses could mean a cure for many viral ailments.
One exciting aspect of these results is that pores of different kinds in membranes are very important for many biological processes, and there are established drugs that interfere with them. We now recognize that this virus, and based on conserved features likely most viruses in this class, depend on similar types of pores to replicate. This is a target we know how to interfere with."
Masaki Nishikiori, the Morgridge Institute for Research
Pore-blocking drugs , also known as channel blockers, have been used in a wide range of diseases such as epilepsies, hypertension, psychiatric disorders, Alzheimer’s disease etc. The team, Nishikiori explained, used biochemical and molecular genetic methods and strategies to explore how these viral mechanisms use the membrane pores.
He explained that they used an advanced bromovirus model that allowed the virus to multiply in yeast cells , providing a controllable system to observe and adapt the virus and host cell activity. They noted that virus anchors or binds to the membrane surfaces of cell organelles and then starts its genome replication process.
In their earlier research, they believed that the process of replication took place in the cytoplasm outside the organelles. Now they noted that the virus must enter the pores to start replicating. Nishikiori said that they found an enzyme called ERO1 that is present only within the organelle on the insides of the membranes.
This enzyme is responsible for promotion of cytoplasmic viral replication. They also noted that there was a viral protein that helped the virus punch holes in the organelle membranes to reach the ERO1 enzyme. If the levels of this enzyme go down, explained Nishikoiri, the viral replication fails and eventually stops.
The building of the pores and bridges also contributes to the oxidation process that helps with replication, the team noted. According to Ahlquist the virus uses strong covalent disulfide bonds that can maintain the replication of the genome. Without these strong bonds, there is a risk of the genomes breaking off before replication is complete.
This research may provide avenues for broad spectrum anti-virals says Ahlquist. At present most of the anti-virals is target or virus specific. A broad spectrum antiviral would be a great benefit for human kind.
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