SARS-CoV-2 Strains

COVID-19, the newest coronavirus to gain international attention, is caused by severe acute respiratory syndrome coronavirus 2. The most common abbreviation for this virus is SARS-CoV-2. As of January 5, 2021, SARS-CoV-2 had infected 85,800,000 people world-wide and caused 1,860,000 deaths. COVID-19 has been the most serious public health emergency of the 21st century so far.

Coronaviruses are a family of viruses named for their crown-like appearance when imaged (corona being the Latin for crown). The large, type I transmembrane spike glycoprotein accounts for this notable feature. It is a heavily-glycosylated, cell-surface protein which is thought to mediate viral entry into susceptible cells. This spike glycoprotein, called ‘S’, is trimeric in structure. In addition to the S protein, there are three other structural base proteins: the envelope, membrane, and nucleocapsid. The S protein has two distinct functional domains, termed S1 and S2, both of which are necessary for a coronavirus to successfully enter a cell.

ACE2 is a receptor of human coronaviruses, such as SARS and HCoV-NL63. It has been determined to be a functional receptor which facilitates the uptake of SARS-CoV-2 into host cells [1-4]. ACE2 is expressed in multiple locations and cell types, notably including alveolar epithelial cells, surface enterocytes within the small intestine, and vascular endothelial cells of the lung, kidneys and heart [5].

SARS-CoV-2 entry into susceptible cells is mediated by the S1 subunit of the coronavirus transmembrane 'spike' glycoprotein. S1 contains a receptor binding domain (RBD) at residues 318–510, which recognises and binds to the LYS341 residue of ACE2 with high affinity [6,7].

The RBD is therefore the critical determinant of virus-receptor interaction and is responsible for infectivity of SARS-CoV-2 viral molecules.

There are several different strains of SARS-CoV-2. The amino acid sequence of the RBD of such strains are largely conserved. In spite of this, over the past number of months, mutations in the RBD have appeared globally that may be the cause of the spread of strains with enhanced infectivity.

In total there are 32 SARS-CoV-2 strains that contain a mutation within the RBD domain of the SARS-CoV-2 molecule [4]. These can be clustered into 9 main types, which are described below.

V367F is one of the most common mutations of the SAR-CoV-2 viral molecule. It has been found in a total of 6 strains globally, and has been causative of the highly infective strains of SARS-CoV-2 found in Hong Kong and France [4]. As the RBD is conserved in SARS-CoV-2, the coincidence of six strains with the same mutation across large geographic distances indicates that this mutant is more robust and that these strains originated as a novel sub-lineage, given the close isolation dates (January 22 and 23 (2020), respectively) [4]. An alternate view is that asymptomatic individuals with the same mutation were “super-infecting” travellers.

By experimental comparison to the prototype spike protein, the spike protein containing the V367F mutation experiences significantly enhanced binding affinity to target receptor, ACE2, thus suggesting enhanced infectivity [4]. This is presumably due to the structural stabilization of the RBD beta-sheet scaffold caused by the V367F mutation [4].

The D614G mutation differs slightly from other SARS-CoV-2 mutations. The D614G mutation is located in the S1 region and is outside of the RBD of the SARS-CoV-2 spike protein. It has been confirmed that the D614G change increases virus infectivity by elevating it's sensitivity to protease and that this mutation has spread widely [8]. This mutation has been observed alongside several of the dominant mutations in the RBD domain, such as V367F, S477N, V483A, K458R ,G485R, A520S, P384L, A522V, and P330S [8]. As explained previously, the V367F mutants were initially discovered in January, 2020 in Hong Kong. Following this, the highly infective D614G+V367F dual mutant was discovered in the Netherlands in March, 2020. This dual mutant spread rapidly and has since been detected mostly in Europe in countries such as United Kingdom, the Netherlands, Spain, Northern Ireland, Switzerland, and Iceland, as well as in the USA, Australia, and Taiwan [4].

This mutation, although one of the most common mutations observed of the SARS-CoV-2 viral molecule, has been witnessed only in co-existence with the D614G mutation [9]. Experimentation has been carried out establish if both K458R and D614G mutations increase infectivity of SAR-CoV-2 in a synergistic manner [9]. When assessed, the D614G+K458R strain showed increased infectivity in comparison to the reference spike protein. However, when compared with single D614G variant of SARS-CoV-2, there was no difference in affinity or infectivity. This therefore suggests that although the K458R co-exists with the D614G mutation, it has no effect on infectivity.

The F342L strain of SARS-CoV-2 was found originally in England [4]. Experimental analysis has indicated that the F342L mutant strain demonstrates similar binding affinity to target ACE2 receptors when compared with a prototype SARS-CoV-2 molecule [4]. This suggests that the F342L mutation does not effect infectivity of SAR-CoV-2.

The A435S mutation was originally detected in Finland. Similar to F342L and G475S, the A435S strain has been shown to experience similar affinity to ACE2 as SARS-CoV-2 molecules with non-mutated RBDs [4].

N354D is one of the 'higher affinity' mutants. This strain was first detected in Shenzhen, China [4]. It is most commonly observed as a dual mutant strain alongside D364Y. Experimental analysis has shown D364Y to be the main contributor to the enhanced infectivity of this dual mutant strain [4]. Both mutations have since not been be detected in China or globally. It is speculated this may be due to the strict quarantine regimen implemented in China at the beginning of the pandemic [4].

V483A has been predominantly observed in the U.S.A. It is considered to have similar infectivity than the non-mutated form of SARS-CoV-2. Thirteen sub-lineages of V483A has been detected in the U.S.A. It has often been observed alongside the S1 D614G mutant [8].

Similar to the V483A strain, the G476S strain has been widely detected in the U.S.A. There have been seven sub-lineages of G476S detected. This strain is said to experience similar affinity to ACE2, thus meaning it is similarly infective as SARS-CoV-2 with no mutations in it's RBD [8].

This was one of the original mutant variants detected of SARS-CoV-2. The W436R strain was first detected in Wuhan. It is considered one of the most infective strains of the virus, alongside V367F, N354D/D364Y, and D614G [4]. The W436R mutation within the RBD of SARS-CoV-2 has been shown to increase binding affinity between it and ACE2 due to the stabilization of the beta structure scaffold of the RBD, as caused by the mutation.

COVID-19 is an ongoing public healthcare emergency. To overcome the pandemic and find balance within society, it has been said that identifying changes in viral infectivity is crucial. This may allow regions affected by low infectivity strains to refine quarantine policies so that the process of repairing the economy can begin. Conversely, in regions affected by highly infective strains, more stringent quarantine policies may be implemented to reduce incident cases, hospital admissions, and deaths. In this way, the monitoring of SARS-CoV-2 mutations therefore may be the best approach to curbing the spread of disease. Not only this, but with more research on the variant strains of SARS-CoV-2 will come improved therapies for the treatment of COVID-19.

1. Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., Graham, B. S., & McLellan, J. S. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, N.Y.), 367(6483), 1260–1263. https://doi.org/10.1126/science.abb2507

3. Chen, Y., Guo, Y., Pan, Y., & Zhao, Z. J. (2020). Structure analysis of the receptor binding of 2019- CoV. Biochemical and biophysical research communications, 525(1), 135–140. Advance online publication. https://doi.org/10.1016/j.bbrc.2020.02.071

4. Ou, J. (2020). Emergence of RBD mutations in circulating SARS-CoV-2 strains enhancing the structural stability and human ACE2 receptor affinity of the spike protein. BioRxiv 2020.03.15.991844; doi: https://doi.org/10.1101/2020.03.15.991844

5. Hamming, I., Timens, W., Bulthuis, M. L., Lely, A. T., Navis, G., & van Goor, H. (2004). Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. The Journal of pathology, 203(2), 631–637. https://doi.org/10.1002/path.1570