Newly discovered modifications of the coronavirus RNA offers clues for combatting COVID-19


Jean and Peter Medawar wrote in 1977 that a virus is “simply a piece of bad news wrapped up in proteins.”

The “bad news” in the SARS-CoV-2 case is the new coronavirus carries its mysterious genome in the form of a very long ribonucleic acid (RNA) molecule.

Grappling with COVID-19 pandemic, the world seems to be lost with no sense of direction in uncovering what this coronavirus (SARS-Cov-2) is composed of.

Being an RNA virus, SARS-Cov-2 enters host cells and replicates a genomic RNA and produce many smaller RNAs (called “subgenomic RNAs”).

These subgenomic RNAs are used for the synthesis of various proteins (spikes, envelopes, etc.) that are required for the beginning of SARS-Cov-2 lineage.

Thus, the smaller RNAs make good targets for messing up new coronavirus’s conquering of our immune system.

Though recent studies reported the sequence of the RNA genome, they only predicted where their genes might be, leaving the world still drown in disorientation.

Led by Professors KIM V. Narry and CHANG Hyeshik, the research team of the Center for RNA Research within the Institute for Basic Science (IBS), South Korea, succeeded in dissecting the architecture of SARS-CoV-2 RNA genome, in collaboration with Korea National Institute of Health (KNIH) within Korea Centers for Disease Control & Prevention (KCDC).

The researchers experimentally confirmed the predicted subgenomic RNAs that are in turn translated into viral proteins.

Furthermore, they analyzed the sequence information of each RNA and revealed where genes are exactly located on a genomic RNA.

Not only to detailing the structure of SARS-CoV-2, we also discovered numerous new RNAs and multiple unknown chemical modification on the viral RNAs.

Our work provides a high-resolution map of SARS-CoV-2.

This map will help understand how the virus replicates and how it escapes the human defense system,” explains Professor KIM V. Narry, the corresponding author of the study.

It was previously known that 10 subgenomic RNAs make up the viral particle structure. However, the research team confirmed that 9 subgenomic RNAs actually exist, invalidating the remaining one subgenomic RNA.

Researchers also found that there are dozens of unknown subgenomic RNAs, owing to RNA fusion and deletion events.

“Though it requires further investigation, these molecular events may lead to the relatively rapid evolution of coronavirus. Moreover, we find multiple unknown chemical modifications on the viral RNAs. It is unclear yet what these modifications do, but a possibility is that they may assist the virus to avoid the attack from the host,” says Prof. Kim.

The research team suggests that modified RNAs may have new properties that are different from unmodified RNAs even though they have the same genetic information in terms of RNA base sequence.

They believe if they figure out the unknown characteristics of RNA, the findings may offer a new clue for combatting the new coronavirus. Newly discovered chemical modification will also help to understand the life cycle of the virus.

This shows the lifecycle of sars-cov-2
When the spike protein of SARS-CoV-2 binds to the receptor of the host cell, the virus enters the cell, and then the envelope is peeled off, which let genomic RNA be present in the cytoplasm. The ORF1a and ORF1b RNAs are made by genomic RNA, and then translated into pp1a and pp1ab proteins, respectively. Protein pp1a and ppa1b are cleaved by protease to make a total of 16 nonstructural proteins. Some nonstructural proteins form a replication/transcription complex (RNA-dependent RNA polymerase, RdRp), which use the (+) strand genomic RNA as a template. The (+) strand genomic RNA produced through the replication process becomes the genome of the new virus particle. Subgenomic RNAs produced through the transcription are translated into structural proteins (S: spike protein, E: envelope protein, M: membrane protein, and N: nucleocapsid protein) which form a viral particle. Spike, envelope and membrane proteins enter the endoplasmic reticulum, and the nucleocapsid protein is combined with the (+) strand genomic RNA to become a nucleoprotein complex. They merge into the complete virus particle in the endoplasmic reticulum-Golgi apparatus compartment, and are excreted to extracellular region through the Golgi apparatus and the vesicle. The image is credited to Institute for Basic Science.

Behind the success of the study is the research team’s pairing of two complementary sequencing techniques; DNA nanoball sequencing and nanopore direct RNA sequencing.

The nanopore direct RNA sequencing allows to directly analyze the entire long viral RNA without fragmentation.

Conventional RNA sequencing methods usually require a step-by-step process of cutting and converting RNA to DNA before reading RNA.

Meanwhile, the DNA nanoball sequencing can read only short fragments, but has the advantage of analyzing a large number of sequences with high accuracy.

These two techniques turned out to be highly complementary to each other to analyze the viral RNAs.

“Now we have secured a high resolution gene map of the new coronavirus that guides us where to find each bit of genes on all of the total SARS-CoV-2 RNAs (transcriptome) and all modifications RNAs (epitranscriptome). I

t is time to explore the functions of the newly discovered genes and the mechanism underlying viral gene fusion. We also have to work on the RNA modifications to see if they play a role in virus replication and immune response.

We firmly believe that our study will contribute to the development of diagnostics and therapeutics to combat the virus more effectively,” notes Professor KIM V. Narry.


Autopsy or biopsy studies would always be the key to understand the biological features of 2019-nCoV. Histological examinations of two patients underwent lung lobectomies for adenocarcinoma, revealed edema, proteinaceous exudate, focal hyperplasia of pneumocytes with only patchy inflammatory cellular infiltration without prominent hyaline membranes.

Since both patients didn’t develop symptoms of COVID-19 pneumonia at the time of surgery, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia. Qian et al. (2020) first reported the pathological characteristics of a patient who died from COVID-19.

General observation from raw eyes showed less fibrosis and consolidation, instead more exudative lesions in COVID-19 than SARS. Microscopic examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates, indicating ARDS.

Interstitial mononuclear inflammatory infiltrates were dominated by lymphocytes. Multinucleated syncytial cells with atypical enlarged pneumocytes showed viral cytopathic-like changes, without obvious intranuclear or intracytoplasmic viral inclusions.

Results from flow cytometric analysis demonstrated that the counts of peripheral CD4+ and CD8 + T cells were substantially reduced, while their status were hyper-activated. It indicated the severe immune injury in later stage of COVID-19, but not by virus direct destruction(Xu et al., 2020b).

Based on the public database and single-cell RNA-Seq technique, pathological studies revealed that male donors had a higher ACE2-expressing cell ratio than their female counterparts.

The only Asian male specimen has five more times as much as ACE2 expressing on the white and African American donors. This might explain why the 2019-nCov and previous SARS-CoV pandemic were concentrated in the Asian population and a heightened susceptibility of male patients, although more evidence was needed to draw such conclusion(Yu et al., 2020).

Pathological manifestations of SARS and MERS infected patients may shed lights to control current 2019-nCoV pandemic. Histology examination demonstrated a considerably higher viral load of SARS-CoV RNA in lung and small bowels than other organs of the body, suggesting an reason for manifestation of pneumonia and diarrhea in SARS patients. Living 2019-nCoV was also detected positive in stool specimens and rectal swabs of infected patients, indicating possible transmission route of oral-faecal transmission.

Proper handling with the infected corpse and disposal of human excreta of infected patients were of great importance(Nicholls et al., 2003). Thrombi were seen in all six autopsies of SARS-CoV infected patients, with even huge thrombus formation in part of pulmonary vessels.

Coagulation function disorders were reported in most of the severe COVID-19 patients, by elevated levels of D-Dimer and prolonged prothrombin time, some of whom ended in disseminated intravascular coagulation(Chen et al., 2020a, Huang et al., 2020, Wang et al., 2020a). This may explain some sudden death of clinical recovery patients and serve as an indicatio

n for disease severity. In an autopsy study, the only one patient without usage of corticosteroids demonstrated increased CD3+ lymphocyte than five other specimen treated by corticosteroids (Pei and Gao, 2005).

It suggested an inhibition of immune system and a careful usage of corticosteroids in COVID-19 treatment. Much is to be discovered in more 2019-nCoV autopsies.


There are currently no vaccine or specific effective antiviral therapies for COVID-19 in general. Thus there is an urgent need for global surveillance of COVID-19 patients. New therapeutic drugs are emerging one after another.

However, double-blinded randomized controlled trials with larger sample size are needed to determine the safety and efficacy of these new drugs and guide clinical decision. Medical interventions can be divided into four major categories: general treatment, coronavirus specific treatments, antiviral treatments and others.

General treatments included nutritional interventions, immuno-enhancers and Chinese medicine. Interferon, intravenous gamma-globulin and thymosin were believed to boost our immune system to fight with SARS-CoV and MERS-CoV as well as 2019-nCoV.

Chloroquine, an old Chinese medicine for treatment of malaria and autoimmune disease, had demonstrated remarkable inhibition in the spread of SARS-CoV by interfering with ACE2 in Vero E6 cell lines(Vincent et al., 2005).

Wang et al. (2020b) demonstrated that chloroquine functioned at both entry and post-entry stages of the 2019-nCoV infection in Vero E6 cells, as well as an immune-modulating activity that enhanced antiviral effect in vivo.

Recent multicenter clinical trails conducted in China have also reported obvious efficacy and acceptable safety in COVID-19 patients by reducing exacerbation of pneumonia, improving radiological findings, promoting a virus negative conversion, and shortening the disease course(Gao et al., 2020).

Due to the indispensable role of the S-protein in coronavirus, therapies and vaccine exploration targeting S-protein-ACE2 interaction may be very promising. Previous therapies targeting SARS-CoV and MERS-CoV may accelerate the development of treatment of COVID-19 because of their structure resemblance and genome similarities.

The human monoclonal antibody could efficiently neutralize SARS-CoV and inhibit syncytia formation between S-protein and ACE2 expressing cells(Sui et al., 2004). Appropriate modification of the monoclonal antibody may be effective for treatment of COVID-19.

What’s more, potential therapies targeting the renin-angiotensin system, to increase ACE2 expression and inhibit ACE may be developed to treat COVID-19 in the future. Hoffmann et al. (2020) reported a cellular protease TMPRSS2 for 2019-nCoV priming upon entrance into cells and viral spread in the infected host cells.

The serine protease inhibitor camostat mesylate against TMPRSS2, can efficiently blocked 2019-nCoV-S-protein-driven cell entry, which could be a promising treatment for 2019-nCoV infection.

There are no effective antiviral treatment for coronavirus infection, even the strong candidates as lopinavir/ritonavir and abidol exhibited no remarkable effect on clinical improvement, day 28 mortality or virus clearance(Chen et al., 2020).

Expectation and attention were shifted to “remdesivir” which may be the most potential wide-spectrum drug for antiviral treatment of 2019-nCoV. Remdesivir is an adenosine analogue, which incorporates into novel viral RNA chains and results in pre-mature termination.

It is currently under clinical development for the treatment of Ebola virus infection(Mulangu et al., 2019). Wang et al. (2020b) revealed that remdesivir were highly effective and safe in the control of 2019-nCoV infection in Vero E6 cells and Huh-7 cells.

A successful appliance of remdesivir on the first 2019-nCoV infected case in the United States when the his clinical status was getting worsen, were recently released(Holshue et al., 2020).

Animal experiments also showed superiority of remdesivir over lopinavir/ritonavir combined with interferon-β, by reducing MERS-CoV titers of infected mice and improving the lung tissue damage(Sheahan et al., 2020).

The effectiveness and safety of remdesivir can be expected by the clinical trial lead by Dr Bin Cao.

The 2019-nCoV infection is associated with a cytokine storm triggered by over-activated immune system(Huang et al., 2020, Xu et al., 2020b), similar to SARS and MERS. The aberrant and excessive immune responses lead to a long-term lung function and structure damage in patients survived from ICU.

Ongoing trials of IL-6 antagonist tocilizumab, which shown effective against cytokine release syndrome resulting from CAR-T cell infusion against B cell acute lymphoblastic leukemia, may be expanded to restore T cell counts and treat severe 2019-nCoV infection(Le et al., 2018).

The available observational studies and meta-analysis of corticosteroid treatment suggested impaired antibody response, increased mortality and secondary infection rates in influenza, increased viraemia and impaired virus clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors(Zumla et al., 2020).

Therefore, corticosteroid should not be recommended for treatment of 2019-nCoV, or use on severe patient with special caution. A review on convalescent plasma for treatment of SARS-CoV and severe influenza infection, suggested a reduction in hospital stay and mortality rate, especially when administered early after symptom onset (Mair-Jenkins et al., 2015).

However, another study demonstrated no significant improvement of convalescent plasma transfusion on survival of Ebola virus infected patients. Possible reasons may be the unknown levels of neutralizing antibodies in convalescent plasma and transfusion timing(van Griensven et al., 2016)

. In terms of vaccine, if any cross-reactive epitopes were identified between 2019-nCoV and SARS-CoV, previous vaccine for SARS-CoV might be re-utilized to facilitate 2019-nCoV vaccine development.

We recommend an influenza and Streptococcus pneumoniae vaccination for prophylaxis, especially in elderly adults(Chen et al., 2020b).

Both pandemic viruses result in similar respiratory symptoms and hard to distinguish. The 2019-nCoV pandemic initiated in flu season which easy to develop a combination infection of 2019-nCoV and influenza or Streptococcus infection. Vaccination against influenza and Streptococcus pneumonia in vulnerable elderly people with comorbidities are highly cost-effective, which is demonstrated to associate with reductions in the risk of hospitalization and death from all causes during influenza seasons(Nichol et al., 2003).

Institute for Basic Science


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