Prior to now 4 years, the pathogen answerable for Coronavirus Illness 2019 (COVID-19), SARS-CoV-2, has contaminated greater than 770 million individuals and prompted greater than 6.9 million deaths worldwide. The extreme impression of SARS-CoV-2 is commonly attributed to its skill to suppress the interferon (IFN) response whereas concurrently inducing the manufacturing of varied cytokines.
To deal with this query, a analysis group led by Prof. Xue Yuanchao from the Institute of Biophysics of the Chinese language Academy of Sciences, along with their collaborators, has profiled the SARS-CoV-2-to-host RNA–RNA interactions.
This research, printed in Molecular Cell on Dec. 20, unveils for the primary time the molecular intricacies of how SARS-CoV-2 RNA interacts with and stabilizes host mRNAs, finally triggering the cytokine storm.
Utilizing state-of-the-art RIC-seq know-how, the researchers comprehensively mapped the SARS-CoV-2-to-host RNA–RNA interactions in contaminated cells and lung tissues obtained from two deceased COVID-19 sufferers. Via mass spectrometry evaluation of the RNA pull-down assay, they found that SARS-CoV-2 RNA varieties base pairs with the three′ UTR of host mRNAs and recruits the RNA-binding protein YBX3 to stabilize host mRNAs in A549-ACE2 and Vero cells. Importantly, interference with the SARS-CoV-2-to-host RNA–RNA interplay or the knockdown of YBX3 considerably diminished host mRNA stability and hindered SARS-CoV-2 replication.
Among the many stabilized host mRNAs, NFKBIZ emerged as a key consider selling cytokine manufacturing and suppressing IFN responses, probably contributing to the cytokine storm. Pulling down NFKBIZ resulted in a big lower within the expression ranges of proinflammatory components akin to IL-6, IL-8, and CXCL2, whereas the degrees of kind I/III IFNs, together with IFNB1, IFNL1, and IFNL2, elevated. These findings counsel that SARS-CoV-2 could induce a cytokine storm by way of stabilized host mRNAs, with NFKBIZ taking part in a pivotal position.
This analysis not solely sheds mild on the regulatory position of RNA–RNA interactions within the immunopathogenesis of RNA viruses akin to SARS-CoV-2, but additionally contributes to the event of novel methods to fight COVID-19.
The outcomes open new avenues for focused interventions aimed toward disrupting the particular molecular mechanisms answerable for the cytokine storm related to extreme instances of COVID-19.
Extra data: Hailian Zhao et al, SARS-CoV-2 RNA stabilizes host mRNAs to elicit immunopathogenesis, Molecular Cell (2023). DOI: 10.1016/j.molcel.2023.11.032