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Exploring the landscape of biomolecular condensates in enterovirus infection

Project description

Unravelling enterovirus-host interactions for antiviral targets

Enteroviruses, a genus that includes pathogens such as poliovirus and rhinovirus, cause diseases ranging from mild colds to severe, life-threatening conditions. Vaccinating against all enteroviruses is impractical due to their vast number, highlighting the urgent need for pan-enterovirus antiviral drugs. While mammalian cells deploy antiviral mechanisms such as stress granules (SGs) to curb viral replication, enteroviruses counteract these defences using the 2A protease (2Apro). However, critical gaps remain in understanding how these cellular defences operate and are subverted by viruses. Supported by the Marie Skłodowska-Curie Actions programme, the BARONET project seeks to unravel the dynamics of antiviral condensates in enterovirus-infected cells. Using advanced microscopy, it aims to uncover virus-host interactions and identify potential therapeutic targets for innovative antiviral strategies.

Objective

The genus Enterovirus comprises many important human pathogens (e.g. polio-, coxsackie-, and rhinovirus) that cause a wide array of diseases ranging from mild to life-threatening. As there are hundreds of enteroviruses and vaccination to all of these is not feasible, there is an unmet need for pan-enterovirus antiviral drugs. Hence, we need to deepen our knowledge on the enterovirus life cycle and virus-host interactions.
Mammalian cells express an arsenal of sensors that function to restrict virus replication and spreading. These include RIG-I and MDA5, which recognize viral RNA and trigger expression of type I interferon (IFN), and PKR, a kinase that upon recognition of viral RNA blocks translation and triggers the formation of membrane-less condensates, so-called stress granules (SGs), that serve as platform for RIG-I and MDA5 signaling. On the other hand, viruses have developed sophisticated mechanisms to suppress antiviral responses. The enterovirus 2A protease (2Apro) has been recognized by the host lab to antagonize SG formation and IFN-gene transcription.
Emerging evidence points towards the existence of many more types of condensates with a role in antiviral signaling, such as PKR clusters, RNase L bodies, and cGAS foci. Unfortunately, comprehensive insight into the composition, formation, and dynamics of these condensates in infected cells are missing. In this project, I aim to comprehensively characterize antiviral condensates in cells infected with wild-type enterovirus or a 2Apro inactive mutant. I will use state-of-the-art microscopy approaches, including an assay that was recently developed by the host lab and that allows real-time visualization of the viral life cycle. Besides, I will assess the role of condensates as signaling platforms that connect stress sensors with effectors of the innate immune response in infected cells. This project will provide insights into enterovirus-host interactions and may uncover new targets for antiviral therapy.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

UNIVERSITEIT UTRECHT
Net EU contribution

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€ 187 624,32
Address
HEIDELBERGLAAN 8
3584 CS Utrecht
Netherlands

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Activity type
Higher or Secondary Education Establishments
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Total cost

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