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The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is distinctly different from outbreaks caused by other coronaviruses: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). The differences in the rapid transmission and severity of human coronaviruses are due to the genetic composition of the virus. SARS-CoV-2 contains genes encoding non-structural proteins (NSPs), structural proteins, and accessory proteins. The NSPs are mainly involved in replication of the virus within the host and inhibition of the host defence system. Structural proteins are involved in viral entry and attachment to host cells, preservation of the core virion and elicit the majority of the immune response. The functions of the accessory proteins are largely unknown. Most focus has been given to structural proteins, especially the spike protein as the strongest vaccine candidate. However, the recent emergence of spike variants and their ability to rapidly transmit and escape neutralisation by vaccine-induced antibodies has threatened the global community. Meanwhile, recent studies of accessory proteins reveal their importance in viral pathogenesis. Hence, proper understanding of the functions of all unknown viral proteins is crucial to devise alternate antiviral strategies.
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Genes of SARS-CoV-2 and emerging variants
Sudip Dhakal
A
and Ian Macreadie
A,B
A
School of Science, RMIT University, Bundoora, Vic. 3083, Australia.
B
Tel.: +61 402 564 308; Email: ian.macreadie@rmit.edu.au
Abstract. The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is distinctly different
from outbreaks caused by other coronaviruses: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).
The differences in the rapid transmission and severity of human coronaviruses are due to the genetic composition of the
virus. SARS-CoV-2 contains genes encoding non-structural proteins (NSPs), structural proteins, and accessory proteins.
The NSPs are mainly involved in replication of the virus within the host and inhibition of the host defence system. Structural
proteins are involved in viral entry and attachment to host cells, preservation of the core virion and elicit the majority of the
immune response. The functions of the accessory proteins are largely unknown. Most focus has been given to structural
proteins, especially the spike protein as the strongest vaccine candidate. However, the recent emergence of spike variants
and their ability to rapidly transmit and escape neutralisation by vaccine-induced antibodies has threatened the global
community. Meanwhile, recent studies of accessory proteins reveal their importance in viral pathogenesis. Hence, proper
understanding of the functions of all unknown viral proteins is crucial to devise alternate antiviral strategies.
Received 15 February 2021, accepted 24 February 2021, published online 9 April 2021
Introduction
The COVID-19 pandemic, caused by the member of Coronaviridae
family, Orthocoronavirinae subfamily, Betacoronavirus genus and
subgenus Sarbecovirus, has severely affected human lifestyles all
around the globe
1
. Owing to its high similarity to the severe acute
respiratory syndrome coronavirus (SARS-CoV), the virus was
named SARS-CoV-2. Disease caused by the virus varies from
asymptomatic to severe and frequently fatal pneumonia. Inadequate
measures to control the virus, combined with its high infectivity,
have had serious consequences for public health worldwide.
Genes of SARS-CoV-2
Coronaviruses are small, 80-220 nm diameter, enveloped, positive
sense, single-stranded RNA viruses that replicate within the
cytoplasm of host cells using the host endoplasmic reticulum and
Golgi network for processing of the proteins and assembly of the
virus
2,3
. The 30 kb genome sequence of the SARS-CoV-2 virus has
15 open reading frames (ORF) that encode nearly 29 proteins
(Figure 1)
2,4
. At the 50end of the viral genome are ORF1a and
ORF1b, encoding polyproteins that are proteolytically processed
into 16 non-structural proteins (NSP1 to NSP16). The non-structural
proteins play vital roles in creating a suitable environment for viral
invasion and replication by hijacking the host protein synthesis
machinery, inhibiting host mRNA expression and antiviral
defences
5
. Detailed descriptions of the functions of the majority of
the SARS-CoV-2 proteins are reviewed elsewhere
4
.Atthe3
0end are
13 ORFs that encode four structural proteins (spike protein (S),
envelope protein (E), nucleocapsid protein (N) and membrane
protein (M)) and nine accessory proteins. Among the structural
proteins, the trimeric S protein (composed of two subunits S1 and
S2) is crucial for allowing viral attachment. It interacts with the host
cell angiotensin converting enzyme 2 (ACE2) receptor via a receptor
binding domain (RBD) present in the S1 subunit allowing the viral
attachment to host cells and aiding in the fusion of the membrane via
S2 subunit
3
. Importantly the S protein is also the major viral protein
eliciting both humoral and cell-mediated immune responses, making
it an excellent vaccine candidate
6
. However, mutations in the S
protein pose a signicant threat by possible generation of mutant
strains with the potential to escape antibody neutralisation, thus
rendering the current vaccine strategy less effective
710
.
Emerging variants of concern
Several lineages of variants have emerged since the rst case in
Wuhan, China in December 2019, posing greater risks to the global
community due to specic mutations in their spike proteins, causing
the strains to become more virulent and resistant to neutralising
antibodies
11
. The most striking ones are those with mutations at the
MICROBIOLOGY AUSTRALIA, 2021
https://doi.org/10.1071/MA21004
In Focus
The Authors 2021 Open Access CC BY, published (by CSIRO Publishing) on behalf of the ASM A
receptor binding domains, which not only alter the interaction of the
spike proteins with the ACE2 receptor but also reduce afnity
towards human neutralising antibodies (refer to Table 1). Examples of
such variants are the UK variant (B.1.1.7), South African variant
(B.1.351) and the Brazilian variant (P.1), that are currently emerging
as increased threats worldwide.
Future directions
Among the various mutations in new variants of SARS-CoV-2, the
spike mutations K417N, E484K, N501Y, N501T and D614G appear
crucial for determining critical alterations in viral behaviour. Muta-
tions that occur in the RBDs of spike proteins cause serious concerns
as current vaccination strategies are based on the original spike
protein. Currently, there are no antiviral agents that can effectively
inhibit SARS-CoV-2 replication in humans
15
. Considering these
limitations, it is of utmost importance to explore new ways towards
nding strategies to reduce viral proliferation. Some NSPs, non-
spike structural proteins and accessory proteins could be investigat-
ed as these proteins are involved in important steps of viral repli-
cation and pathogenesis such as viral protein synthesis, hijacking
host protein synthesis machinery and inhibiting intracellular host
defence mechanisms
4
. Some such protein targets are NSP1 (inhibits
host mRNA translation), NSP3 (papain like protease that releases
NSP1, NSP2 and NSP3 from viral polyprotein), NSP5 (main pro-
tease that cleaves viral polyproteins into individual functional
proteins), NSP6 (prevents host autophagosome-lysosome fusion)
and N-protein (preserves viral RNA from interfering RNAs from
host).
The functions of the accessory proteins of SARS-CoV-2 are
largely unknown and further investigations uncovering their role
may shed light on the unanswered questions of rapid spread and
differences in disease severity of SARS-CoV-2. Several accessory
proteins are been investigated for their role during viral invasion. In
a recent study comparison of the proteins encoded by SARS-CoV-2
with the proteins of SARS-CoV revealed the presence of novel
ORF8 and ORF10 proteins in SARS-CoV-2. Structural analysis of
ORF8 protein supported the claim that the protein can form unique
large-scale assemblies that are not present in SARS-CoV, potentially
inhibiting the host defence system
16
. Additionally, association of
ORF8 deletion variant (D382 variant) with milder disease outcome
strongly supports the importance of ORF8 protein as a therapeutic
target against SARS-CoV-2
17
. Meanwhile, ORF10 is the only
protein that is not present in other human coronaviruses and is yet
to be studied. Nucleotide sequences similar to ORF10 were found in
SARS-CoV but with a nonsense mutation, causing early termination
of protein synthesis
18
. Further analysis of the predicted structure of
the ORF10 protein showed a signal peptide and a hydrophobic
Figure 1. Schematic diagram showing genome of SARS-CoV-2. Green coloured genes encode polyproteins that are proteolytically cleaved into non-
structural proteins (NSP), red coloured genes encoding structural proteins and blue coloured genes encoding accessory proteins.
Table 1. Emerging SARS-CoV-2 variants of concern and their effect on viral pathogenesis.
Emerging variants Lineage Spike protein mutation Viral pathogenesis of variant Reference
South African variant 20H/501Y.V2 or
B.1.351
L18F, D80A, D215G, R246I, K417N, E484K, N501Y,
D614G, A701V
Increased infectivity and escape from
human neutralising antibodies
9,10
Potential deletion at L242_L244 or mutation L242H
Italian variant MB61 K182N, Q493K, N501T, D614G Alteration in ACE2 binding and escape
from vaccine induced or natural
neutralising antibodies
12
L242 deletion
UK variant 20I/501Y.V1, VOC
202012/01, or
B.1.1.7
N501Y, A570D, P681H, T716I, S982A, D1118H Increased transmissibility, disease
severity
8,13
Y144 deletion, H69_V70 deletion
Brazilian variant P.1 or 20J/501Y.V3) L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y,
H655Y, T1027I
Alteration in ACE2 interaction and
human antibody; increased resistance
to neutralising antibodies
8,14
In Focus
BMICROBIOLOGY AUSTRALIA *2021
b-sheet region beyond the cleavage site, suggesting a possible
hydrophobic interaction and membrane localisation, maybe as trans-
port protein. These ndings suggest ORF10 proteins possible role in
viral invasion, which needs to be explored further
18
.
Other accessory proteins differ in their effect and activity despite
a high similarity in protein sequence alignment. A recent study
comparing the ability of ORF3a proteins of SARS-CoV-2 and
SARS-CoV to induce apoptosis showed reduced induction of cell
death by SARS-CoV-2 protein
19
. These differences in the viral
proteins could explain the differences in the severity of the
SARS-CoV-2 and SARS-CoV. Further research and new insights
in the potential role of accessory proteins during viral invasion could
indicate novel ways to reduce the infectivity, rapid spread and boost
host immune system. Such studies will not only lead to therapeutic
strategies against SARS-CoV-2 virus, but also be useful for similar
viral infections including SARS-CoV and MERS-CoV infections.
Conicts of interest
Ian Macreadie is the Editor-in-Chief of Microbiology Australia but
was blinded from the peer-review process for this paper.
Acknowledgements
This research did not receive any specic funding.
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Biographies
Sudip Dhakal is a PhD candidate at
School of Science, RMIT University
under Biosciences discipline, whose
research focuses on overcoming reduced
proteostasis in Alzheimers disease.
Ian Macreadie is an Honorary Professor
at RMIT University and Editor-in-Chief
of Microbiology Australia. His research
and expertise are in diverse elds of bios-
ciences ranging from industrial microbi-
ology to biomedical research.
In Focus
MICROBIOLOGY AUSTRALIA *2021 C
... kb [1,2]. Patients with COVID-19 demonstrate symptoms ranging from common cold-like symptoms to severe symptoms in multiple organs and, in some cases, death [3]. According to the serotype and genomic classification, there are four Coronavirinae subfamily variants of concern (VOC) reported by the World Health Organization (WHO, Alpha (B.1.1.7), ...
... Compared to SARS-CoV and MERS-CoV, the SARS-CoV-2 genome has 82% sequence identity overall, and over 90% sequence identity for structural proteins and essential enzymes [9]. According to the NCBI annotation, (NC_045512), SARS-CoV-2 has 14 functional open reading frames (ORFs), which encode up to 31 proteins, shown schematically in Figure 1 [3,10]. The first ORFs, ORF1a and ORF1b, are the longest ORFs and occupy more than two thirds of the whole genome [3,11]. ...
... According to the NCBI annotation, (NC_045512), SARS-CoV-2 has 14 functional open reading frames (ORFs), which encode up to 31 proteins, shown schematically in Figure 1 [3,10]. The first ORFs, ORF1a and ORF1b, are the longest ORFs and occupy more than two thirds of the whole genome [3,11]. Polyproteins 1a and 1b are encoded by ORFs 1a and 1b. ...
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