Uncovering the essential role of host hetero-hexameric ATPases in rhinovirus replication
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Medicine, Dentistry & Biomed Sci
Abstract
Rhinoviruses are responsible for most common colds, causing billions of infections in humans every year across the globe. Although rhinovirus infections are associated with huge health, economic and social costs, there is no approved antiviral or vaccine against rhinoviruses. So far, around 170 different varieties of rhinoviruses have been identified and all efforts to make an effective vaccine have failed to date. Attempts to make antiviral drugs that directly target the virus have not been effective neither, partly because rhinoviruses are able to mutate very easily, and quickly develop resistance.
As rhinoviruses need to enter and interact with host cells to multiply, a new strategy for making an antiviral drug may be to target the interactions between the virus and the host cells, rather than the virus itself. For this kind of antiviral strategy, we first need to understand how the virus interacts with host cells and uses them to reproduce. This area of research is still not very well understood for rhinoviruses, but also many related pathogenic viruses like poliovirus. Therefore, any discovery in this area promises to also help our understanding of other related viruses, which often use similar mechanisms to interact with host cells to reproduce.
This project will investigate aspects of the interactions of rhinoviruses with host cells that have never been studied. This exciting project builds on a previous project funded by the Medical Research Foundation and Asthma UK.
To reproduce in host cells, rhinoviruses build inside the cells that they infect some virus factories where new viruses are produced. These virus factories contain some viral proteins and some human proteins that are hijacked by the viral proteins to help them produce new viruses. While we know which are the viral proteins involved, we still do not know all the human proteins that are hijacked and enable the virus to reproduce. During our previous project, we have identified some host proteins that are in physical contact with the viral proteins. In particular, 2 of them seem to be absolutely necessary for the virus to reproduce. By removing them from the cells or blocking them with chemicals, the virus cannot reproduce anymore. This discovery is very exciting and could lead, in the long term, to new strategies to block the multiplication of the virus in host cells. But we first need to understand in great detail how these host proteins allow the virus to reproduce. This project will investigate that.
We will examine, in the different steps that the virus uses to reproduce, exactly which one(s) need the host protein that we identified. We will precisely analyse which of the viral proteins bind to the host proteins that we identified and how these interactions happen and play an important role in the virus factories, to make new copies of the virus.
All this will give us a good understanding of how the virus uses these host proteins to reproduce in cells. This will help us to better understand how rhinoviruses, which have evolved with humans since thousands of years, use our cells in very efficient ways to reproduce, something that happens in each of us every year. In turn, this knowledge will help to design new molecules that could block this and therefore prevent the virus to reproduce.
As rhinoviruses need to enter and interact with host cells to multiply, a new strategy for making an antiviral drug may be to target the interactions between the virus and the host cells, rather than the virus itself. For this kind of antiviral strategy, we first need to understand how the virus interacts with host cells and uses them to reproduce. This area of research is still not very well understood for rhinoviruses, but also many related pathogenic viruses like poliovirus. Therefore, any discovery in this area promises to also help our understanding of other related viruses, which often use similar mechanisms to interact with host cells to reproduce.
This project will investigate aspects of the interactions of rhinoviruses with host cells that have never been studied. This exciting project builds on a previous project funded by the Medical Research Foundation and Asthma UK.
To reproduce in host cells, rhinoviruses build inside the cells that they infect some virus factories where new viruses are produced. These virus factories contain some viral proteins and some human proteins that are hijacked by the viral proteins to help them produce new viruses. While we know which are the viral proteins involved, we still do not know all the human proteins that are hijacked and enable the virus to reproduce. During our previous project, we have identified some host proteins that are in physical contact with the viral proteins. In particular, 2 of them seem to be absolutely necessary for the virus to reproduce. By removing them from the cells or blocking them with chemicals, the virus cannot reproduce anymore. This discovery is very exciting and could lead, in the long term, to new strategies to block the multiplication of the virus in host cells. But we first need to understand in great detail how these host proteins allow the virus to reproduce. This project will investigate that.
We will examine, in the different steps that the virus uses to reproduce, exactly which one(s) need the host protein that we identified. We will precisely analyse which of the viral proteins bind to the host proteins that we identified and how these interactions happen and play an important role in the virus factories, to make new copies of the virus.
All this will give us a good understanding of how the virus uses these host proteins to reproduce in cells. This will help us to better understand how rhinoviruses, which have evolved with humans since thousands of years, use our cells in very efficient ways to reproduce, something that happens in each of us every year. In turn, this knowledge will help to design new molecules that could block this and therefore prevent the virus to reproduce.
Technical Summary
Rhinoviruses (RVs), which are responsible for most common colds, have evolved very efficient ways to subvert cellular processes to replicate and produce vast amounts of progeny virions in as little as 6 hours of infection, despite a very limited coding capacity (~7 kb). The highly effective virus-host interactions involved are however still poorly understood, for both RVs and related viruses of the picornavirus family.
This proposal will address this knowledge gap by investigating new mechanisms by which RVs hijack a host hetero-hexameric ATPase that we found to play a crucial role in the replication of the virus.
Building on the hypothesis that interactions between host proteins and specific viral proteins, the non-structural proteins (NSPs) that interact with the viral RNA, are critical to orchestrate the exploitation of the host cell machinery, we determined the interactome of RV NSPs in infected cells and analysed the importance of the identified interactors for viral replication. This uncovered that a host hetero-hexameric ATPase that consistently interacted with RV NSPs in infected cells was absolutely essential for RV replication, a role that has never been described for RVs or any related virus.
Based on our preliminary data, we hypothesise that this cellular ATPase plays a critical role in the assembly of viral/host protein complexes on the viral RNA, which are key to enable its replication.
The proposed project will unravel the molecular mechanisms underlying the unprecedented role of this ATPase in the viral replication complexes and define new critical steps in the RV replication cycle. Ultimately, by precisely identifying the key interactions involved and their functional consequences for the replication of the virus, this research will identify key vulnerabilities that could be exploited for the development of novel antiviral strategies that specifically target these virus-host interactions without affecting cellular functions.
This proposal will address this knowledge gap by investigating new mechanisms by which RVs hijack a host hetero-hexameric ATPase that we found to play a crucial role in the replication of the virus.
Building on the hypothesis that interactions between host proteins and specific viral proteins, the non-structural proteins (NSPs) that interact with the viral RNA, are critical to orchestrate the exploitation of the host cell machinery, we determined the interactome of RV NSPs in infected cells and analysed the importance of the identified interactors for viral replication. This uncovered that a host hetero-hexameric ATPase that consistently interacted with RV NSPs in infected cells was absolutely essential for RV replication, a role that has never been described for RVs or any related virus.
Based on our preliminary data, we hypothesise that this cellular ATPase plays a critical role in the assembly of viral/host protein complexes on the viral RNA, which are key to enable its replication.
The proposed project will unravel the molecular mechanisms underlying the unprecedented role of this ATPase in the viral replication complexes and define new critical steps in the RV replication cycle. Ultimately, by precisely identifying the key interactions involved and their functional consequences for the replication of the virus, this research will identify key vulnerabilities that could be exploited for the development of novel antiviral strategies that specifically target these virus-host interactions without affecting cellular functions.
