COVID-19 – Genomics Research to Understand the SARS-CoV-2 Pandemic further

By Vinay CG, Sr. Manager – Content & Communications, Peer Reviewers: Kushal Suryamohan (Bioinformatics Scientist) & Hiranjith GH (Senior Director, Corporate Marketing & Business Operations ), MedGenome Inc., USA

COVID-19 caused by SARS-CoV-2 Virus has emerged as a major challenge with no known vaccine available in the market so far. This pandemic has warranted scaling up of research efforts both by pharma companies and university research centres to develop a viable vaccine. Although there are many promising candidates in the pipeline, none will be available anytime soon making social distancing measures and quarantine as the only effective resort to contain this disease.

The virus itself is zoonotic in its origin, capable of jumping from its natural host, bats, to other species, including humans. Phylogenetic analyses of viral genome sequences have indicated that it closely resembles SARS-like coronavirus strain BatCov RaTG13¹ and that it spread to human population through an intermediary host, likely pangolins.

Structure and Entry

The novel coronavirus is made up of a Nucleocapsid Protein (N), Spike Proteins (S), Envelope Protein (E) and the Membrane Protein (M) – see Figure 1.

The S-protein is the most critical one as it binds to the host cell receptor thus entering the host cell. Specifically, in humans the β-coronaviruses – the class to which the previous SARS-CoV and the current SARS-CoV-2 belong to – are found to bind to Angiotensin-converting Enzyme Receptor 2 (ACE2). The S- protein consists of 2 sub-units namely the S1 and the S2. The S1 sub-unit (receptor binding domain (RBD)) binds with the host cell receptor while the S2 sub-unit helps in fusing the viral and host membranes³. This process is aided by a cellular serine protease TMPRRS2– which helps in S-protein priming⁴. Once the virus’s viral RNA genome enters the cytoplasm it gets translated into two polyproteins and structural proteins, and then the viral genome begins to replicate. This is followed by the insertion of newly formed glycoproteins into the membrane of endoplasmic reticulum (ER) or the Golgi complex thus leading to the formation of the nucleocapsid owing to the combination of genomic RNA and nucleocapsid protein. The viral particles then germinate into the ER-Golgi intermediate compartment (ERGIC) and finally the vesicles containing virus particles fuse with the plasma membrane to release the virus⁵ (Figure 2⁶).

Clinical Features and Pathogenicity

SARS-CoV-2 viral infection is primarily through respiratory droplets. Infected individuals may exhibit fever, cough, and fatigue, while other symptoms include sputum production, headache, haemoptysis, diarrhoea, dyspnoea, and lymphopenia⁷. However, the incubation period may range from 1 to 14 days before a patient can display any symptoms.

Replication is usually in mucosal epithelium of upper respiratory tract (nasal cavity and pharynx), with further multiplication in lower respiratory tract and gastrointestinal mucosa.

Possible Drug Targets

The thorough understanding of the underlying mechanisms of SARS-CoV-2 is proving to be a vital key for the development of novel drugs and vaccines against this virus. Possible approaches for discovery of drugs/vaccine are shown in Figure 4⁹.

MedGenome Study, Services and Genomic Solutions

I. SARS-CoV-2 Virus and Structural evaluation of Human ACE2 receptor polymorphism

MedGenome recently performed an extensive analysis to identify ACE2 polymorphisms that might alter host susceptibility to SARS-CoV-2 by affecting the ACE2-S-protein interaction. This comprehensive analysis included several large genomic datasets that included over 290,000 samples representing >400 population groups and identified multiple ACE2 protein-altering variants, some of which mapped to the S-protein-interacting ACE2 surface. Using recently reported structural data and a recent S-protein interacting synthetic mutant map of ACE2, our scientists could identify natural ACE2 variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs. Other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein.

To know more about the study, please click here to access our publication.

II. MedGenome COVID-19 research services and solutions

MedGenome also offers critical services out of our high-throughput Next-Generation sequencing lab in Foster City, California, to help manage and accelerate our customer’s COVID-19-related R&D projects.

Highlights of MedGenome’s services:

• BCR & TCR repertoire from patients and healthy individuals
• Bulk RNA sequencing and genome assembly of the virus
• Host genome sequencing, variant calling and annotation in key pathway genes
• Cloning and in-vitro assays to test antibody and vaccine candidates
• Customized genotyping array capturing common and rare ACE2 and TMPRSS2 coding variants for exploring host genetics

To know more about our services, please click here

References

1. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
2. Seah, I., Su, X. & Lingam, G. Revisiting the dangers of the coronavirus in the ophthalmology practice. Eye (2020). https://doi.org/10.1038/s41433-020-0790-7
3. Fang Li, Structure, Function, and Evolution of Coronavirus Spike Proteins, Annu. Rev. Virol. 2016.3:237-261
4. Hoffmann et al., 2020, Cell 181, 1–10, April 16, 2020.
5. X. Li et al., Molecular immune pathogenesis and diagnosis of COVID-19, Journal of Pharmaceutical Analysis, https://doi.org/10.1016/j.jpha.2020.03.001
6. https://www.fpm.org.uk/blog/covid-19-sars-cov-2-pandemic/
7. H.A. Rothan and S.N. Byrareddy, Journal of Autoimmunity 109 (2020) 102433
8. Yuefei Jin et al, Virology, Epidemiology, Pathogenesis, and Control of COVID-19, Viruses 2020, 12, 372.
9. Haibo Zhang et al, Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target, Intensive Care Med (2020) 46:586–590.

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