Researchers reveal molecular mechanism of coronavirus-induced cytokine storm

Over the past four years, the pathogen responsible for coronavirus disease 2019 (COVID-19), SARS-CoV-2, has infected more than 770 million people and caused more than 6.9 million deaths. deaths worldwide. The severe impact of SARS-CoV-2 is often attributed to its ability to suppress the interferon (IFN) response while simultaneously inducing the production of various cytokines.

This dual action directly leads to a cytokine storm, a critical factor contributing to mortality in COVID-19 patients. However, the precise mechanisms by which SARS-CoV-2 triggers this cytokine storm remain elusive.

To answer this question, a research team led by Professor Xue Yuanchao of the Institute of Biophysics of the Chinese Academy of Sciences, along with collaborators, profiled the RNA-RNA interactions of SARS-CoV-2 towards the host.

This study, published in Molecular cell on December 20, unveils for the first time the molecular intricacies of how SARS-CoV-2 RNA interacts with and stabilizes host mRNAs, ultimately triggering the cytokine storm.

Using cutting-edge RIC-seq technology, researchers comprehensively mapped SARS-CoV-2 RNA-RNA interactions toward the host in infected cells and lung tissues obtained from two patients who died from COVID-19. Through mass spectrometry analysis of RNA pull-down analysis, they discovered that SARS-CoV-2 RNA forms base pairs with the 3′ UTR of host mRNAs and recruits the RNA binding protein YBX3 to stabilize host mRNAs in A549-ACE2 and Vero. cells. Importantly, interference with SARS-CoV-2 RNA-RNA interaction toward the host or inactivation of YBX3 significantly reduced host mRNA stability and hindered the replication of SARS-CoV-2.

Among the stabilized host mRNAs, NFKBIZ emerged as a key factor in promoting cytokine production and suppressing IFN responses, potentially contributing to the cytokine storm. Knockdown of NFKBIZ resulted in a significant decrease in the expression levels of pro-inflammatory factors such as IL-6, IL-8, and CXCL2, while the levels of type I/III IFNs, including IFNB1, IFNL1 and IFNL2, increased. These results suggest that SARS-CoV-2 may induce a cytokine storm via stabilized host mRNAs, with NFKBIZ playing a central role.

This research not only highlights the regulatory role of RNA-RNA interactions in the immunopathogenesis of RNA viruses such as SARS-CoV-2, but also contributes to the development of new strategies to combat COVID-19.

The findings open new avenues for targeted interventions aimed at disrupting the specific molecular mechanisms responsible for the cytokine storm associated with severe cases of COVID-19.