COVID-19 Updates: Stanford-Yale Study On Viral Pathogenesis Reveals Viral RNA-Binding Proteins That Protects Human Host From Virus-Induced Cell Death

COVID-19 Updates: A latest research by scientist from Stanford University and Yale University on viral pathogenesis revealed an unexpected new discovery of SARS-CoV-2 viral RNA-binding proteins that protect the host from virus-induced cell death.


 
Utilizing comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), the study team identified 309 human host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with viral ChIRP-MS data from three other positive-sense RNA viruses defined pan-viral and SARS-CoV-2-specific host interactions.
 
Functional interrogation of these factors with a genome-wide CRISPR screen revealed that the vast majority of viral RNA-binding proteins protect the host from virus-induced cell death, and the team identified known and novel anti-viral proteins that regulate SARS-CoV-2 pathogenicity.
 
Interestingly the RNA-centric approach demonstrated a physical connection between SARS-CoV-2 RNA and host mitochondria, which the team validated with functional and electron microscopy data, providing new insights into a more general virus-specific protein logic for mitochondrial interactions.
 
The study findings provide a comprehensive catalogue of SARS-CoV-2 RNA-host protein interactions, which may inform future studies to understand the mechanisms of viral pathogenesis, as well as nominate host pathways that could be targeted for therapeutic benefit
 
The study findings were published on a preprint server and are currently pending peer review. https://www.biorxiv.org/content/10.1101/2020.10.06.327445v1
 
Such a detailed SARS-CoV-2 infection analysis could help fight against COVID-19. The study team provided a detailed catalog of the interactions that occur between host cell proteins and RNA and the RNA of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the course of infection.
 
Simply by integrating the analysis across various time points, species, and other positive single-stranded RNA viruses, the study team has identified both shared and SARS-CoV-2-specific patterns of RNA–host protein interactions.
 
The researchers say the study findings may help to inform future studies aiming to understand viral pathogenesis and potential therapeutic strategies to combating SARS-CoV-2 infection.
 
For a while now, many researchers are urgently trying to understand the molecular mechanisms required for host cell infection and antiviral immunity.
 
Even though the genomes of positive single-stranded RNA viruses share similar replication strategies, there is remarkable variation in the health outcomes these pathogens cause.
 
For example, the mosquito-borne flaviviruses such as Dengue and Zika cause systemic disease, while human coronaviruses such as SARS-CoV-2 generally cause respiratory symptoms.
 
Furthermore the infection process is complex and often highly specific to the individual virus.
 
Upon binding and entering a human host cell, the viral genome remodels host cellular pathways in order to express, replicate, and pr oduce new virions.
Once viral RNA transcripts are deposited in host cells, they eventually produce viral protein products.
 
Co-researchers Dr Ryan Flynn from Stanford University told Thailand Medical News, “Together, these RNA and protein species remodel the cell to facilitate the viral life cycle.”
 
Certain research papers have recently described the viral products encoded by SARS-CoV-2 RNA and their interactions with host partners, but the precise interactions of SARS-CoV-2 viral RNA (vRNA) with host partners are not well understood.
 
The study team has used comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-ms) to define both the shared and SARS-CoV-2-specific host pathways that associate with vRNAs.
 
The researchers identified 309 host proteins that interact with SARS-CoV-2 RNA during the course of infection.
 
Simply by comparing the data with ChIRP-MS data for three other positive-sense RNA viruses (Zika, Dengue, and rhinovirus), as well with genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screens, the researchers identified both shared and SARS-CoV-2-specific patterns of RNA–host protein interactions.
 
For example, the vRNAs of SARS-CoV-2, Dengue, and Zika are all associated with the Rab proteins RAB10 and RAB2A, which are involved in subcellular trafficking, and these proteins are needed for viral replication and virus-induced cell death.
 
In contrast however, although both human coronaviruses and the flaviviruses require these Rab glycoproteins to produce new infectious virions, the interaction of SARS-CoV-2 vRNA with the translational apparatus and the Sec/Translocon/OST complexes was limited, compared with Dengue and Zika.  
 
Dr Flynn added, “These data suggest that while both form membrane-enclosed replication complexes, flaviviruses may physically leverage the translocon complex, while SARS-CoV-2 leverages other domains of the ERGIC [ER-Golgi intermediate compartment]).”
 
Surprisingly an unexpected discovery was that the vast majority of (116/138) of vRNA-binding proteins protected the host from virus-induced cell death, rather than functioning as pro-viral factors.
 
Most of these antiviral factors were bound to multiple viral families, but the researchers also identified 31 that were specific to SARS-CoV-2.
 
Dr Flynn added, “These study results demonstrate that host cells deploy a broad and diverse array of proteins to physically recognize and counteract viral infection.”
 
Significantly the researchers also identified a physical connection between SARS-CoV-2 vRNA and host mitochondria, which was validated by electron microscopy data demonstrating changes in mitochondrial shape and size following infection.
 
The study team points out that other viruses, including HIV, have also been reported to enter the mitochondria, suggesting that vRNA can gain access to the mitochondria during infection.
 
The powerhouse organelles called the Mitochondria, are key to maintaining cellular health, play an important role in sensing and signaling during cellular stress, and are vital for innate immune signaling.
 
The study team noted, “We propose that RNA viruses may follow a distinct logic when causing mitochondrial stress; that is, many viruses may interact with and perturb this organelle, but the precise manner in which stress is caused, and thus signaling occurs, is virus-specific.”
 
The study team says that the research provides an RNA-centric view of the host proteins and RNAs interacting with SARS-CoV-2 RNA during active infection and has identified both shared and SARS-CoV-2-specific patterns of RNA-host protein interactions.
 
The team added, “Altogether, these data provide a comprehensive catalogue of SARS-CoV-2 RNA-host protein interactions, which may inform future studies to understand the mechanisms of viral pathogenesis, as well as nominate host pathways that could be targeted for therapeutic benefit.”
 
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