The ongoing Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has acutely highlighted the need to identify new treatment strategies for viral infections. Recent reports show more than 40 million positive cases of the SARS-CoV-2 infection, with over 1 million lives lost. However, effective antivirals are still not available to mitigate the disease or vaccines to block infection. Therefore, it is critical to understand the viral interactions with the host at the cellular and molecular levels.
An important phase of the viral protein translation relies on the mitochondrial translation machinery. Towards this goal, the molecular mechanism involved in the SARS-CoV-2 entry into human cells is studied by Zhenguo Cheng et al.
The researchers report in a bioRxiv* preprint publication that the virus hijacks the mitochondrial functions. They report that the mitochondrial localization of the viral RNA occurs. It is critical for the translation of SARS-CoV-2 S protein.
SARS-CoV-2 is a single-stranded, positive-sense group β coronavirus, with a genome of around 30kbp. The virus genome contains ten open-reading frames (ORFs) that encode four structural proteins: Spike (S), Membrane (M), Envelope (E), and the nucleocapsid (N) proteins, and six nonstructural proteins ORF1ab, ORF3, ORF6, ORF7, ORF8, and ORF10.
In this study, the researchers explored the protein expression pattern of SARS-CoV-2 and found that several key genes of SARS-CoV-2 show codon usage bias. Further probing the underlying mechanisms responsible may provide a new direction for targeting of antiviral drugs.
It is widely understood that viruses actively interfere with mitochondrial pathways to impede mitochondrial antiviral signaling mechanisms. This study demonstrates that the SARS-CoV-1 ORF-9b localizes to mitochondria to manipulate mitochondrial function. It suppresses the antiviral signaling. This creates mitochondrial stress that acts to promote virus survival and replication. Mitochondrial vesicles are formed, that act as a replication niche for the virus.
The researchers have observed that SARS-CoV-2 controls the spike gene's translation by hijacking host mitochondria through 5' leader and 3' UTR sequences. These sequences contain mitochondrial localization signals and activate the EGR1 pathway.
Mitochondria are dynamic organelles that control a wide range of cellular processes, including ATP generation, cellular differentiation, apoptosis, and antiviral immune activation. Mitochondria show a different codon usage preference from the nuclear genome. The researchers performed a comparison of codon usage bias: key rare codon rates in SARS-CoV-2 and S protein were highly similar to the rate seen in mitochondrial genes, and these rates were much higher than found in the human nuclear genome. They find that rare codon bias can prevent translation of SARS-CoV-2 derived sequences. This study shows that rare codons such as Leu-TTA are highly enriched in many viruses, including SARS-CoV-2, and these codons are essential for regulating viral protein expression. This clarifies the influence of codon bias on the abundance of rare codon rich viral proteins such as SARS-CoV-2 S and Ad11 fiber.
Mitochondrial-targeting drugs have strong potential as antiviral therapeutic reagents. The researchers study lonidamine and polydatin (well-characterized anti-cancer drugs that target mitochondrial pathways to induce cell-death) and their effect on viral replication. They report that these mitochondria-targets significantly repress rare codon-driven gene expression and viral replication.
This detailed study suggests a novel viral protein translation mechanism that relies on the manipulation of the mitochondrial translation apparatus.
The three main avenues of COVID-19 antiviral research are: 1) viral replication inhibitors that target viral proteins; 2) drugs that block host cell proteins involved in viral infection; and 3) reagents that balance host immune responses to infection. The study presented in this paper identifies an unreported viral protein translation mechanism and opens up the fourth avenue for developing antiviral drugs. The authors warrant for immediate clinical trials for testing their application for SARS-COV-2 and other viral infections.
This is an important study expanding our understanding of the role of mitochondria in viral infections. It provides new and possible avenues for the development of antiviral drugs.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- A novel viral protein translation mechanism reveals mitochondria as a target for antiviral drug development, Zhenguo Cheng, Danhua Zhang, Jingfei Chen, Yifan Wu, Xiaowen Liu, Lingling Si, Zhe Zhang, Na Zhang, Zhongxian Zhang, Wei Liu, Hong Liu, Lirong Zhang, Lijie Song, Louisa S Chard Dunmall, Jianzeng Dong, Nicholas R Lemoine, Yaohe Wang, bioRxiv 2020.10.19.344713; doi: https://doi.org/10.1101/2020.10.19.344713 , https://www.biorxiv.org/content/10.1101/2020.10.19.344713v1