Viral ribonucleoproteins
Humans have been in contact with emerging and re-emerging infectious diseases since hundreds of years, however recent indications suggest that the frequency and severity of such diseases are rapidly increasing. Considering that two third of such illness are caused by RNA viruses, such as dengue fever (DENV), severe pneumonia (SARS-Cov-2), and polyarthritis (CHIKV), investigating this group of pathogens is vital to predict and manage the severity of any incoming emerging viruses. Considering that the genetic material for these pathogenic viruses is RNA with limited coding capacity, host RNA binding proteins are hijacked to facilitate different viral processes including viral RNA transcription, translation and virions assembly. Here we focus on mosquito-borne diseases, which has expanded dramatically in the last few decades to become an emerging global health problem, with around 1 billion new infections and 1 million deaths each year. I propose a workflow composed of number of unbiased, cutting edge, high-throughput techniques with three main objectives 1) determining the RBPome of mosquito cells 2) identification of the complement of mosquito RBPs involved in virus infection 3) role of selected mosquito RBPs in viral infection.
Moreover, the overall objective of the proposed work is to create a workflow not relying on prior detailed knowledge about host-virus interactions, consequently it offers to be an unprecedented unbiased approach that is well-suited for investigating emerging virus infections
Why
Viral Ribonucleoproteins, are a set of proteins involved in regulating different aspect of virus life cycle such as translation, replication and transcription, processing and stability, and acting as scaffold for numerous pro and antiviral interactions. Thus, identifying vRNPs is the key to understand different stages of virus life cycle, and additionally it presents a set of potential antiviral.targets.
Project outcomes
Developing a viral RNA interactome capture: I have developed the viral RNA interactome capture, which is a widely applicable technique to identify proteins binding specifically to viral RNA. I applied this technique in both mosquitos and human cells with wide range of viruses including Sindbis and SARS-CoV2. The significance of identifying proteins binding to viral RNA can be summarized in two aspects 1) they reflect the proteins involved in processing viral RNA leading to better understanding of the virus life cycle 2) due to their direct interaction with viral RNA, they are highly likely to be essential for virus infection thus presenting numerous for therapeutic interventions (which I show in the presented publications as well)
Applying the DRmov workflow on newly emerging virus infections: At the time of writing the fellowship application at 2018, I presented DRmov as standalone workflow composed of number of consequential techniques to address lack of information about emerging viruses and poorly-studied vectors. With emergence of SARS-CoV2 and dominance of COVID19 in 2020, I applied the DRmov workflow to such threat. This work (which is award winning and published in Molecular cell) presented details about SARS-CoV2 life cycle and provided several opportunities for therapeutic intervention.
