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Review
. 2021 Jul 14:12:682603.
doi: 10.3389/fmicb.2021.682603. eCollection 2021.

Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes?

Nathalie Chazal  1
Affiliations
Review

Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes?

Nathalie Chazal. Front Microbiol. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that emerged in late 2019, is the etiologic agent of the current "coronavirus disease 2019" (COVID-19) pandemic, which has serious health implications and a significant global economic impact. Of the seven human coronaviruses, all of which have a zoonotic origin, the pandemic SARS-CoV-2, is the third emerging coronavirus, in the 21st century, highly pathogenic to the human population. Previous human coronavirus outbreaks (SARS-CoV-1 and MERS-CoV) have already provided several valuable information on some of the common molecular and cellular mechanisms of coronavirus infections as well as their origin. However, to meet the new challenge caused by the SARS-CoV-2, a detailed understanding of the biological specificities, as well as knowledge of the origin are crucial to provide information on viral pathogenicity, transmission and epidemiology, and to enable strategies for therapeutic interventions and drug discovery. Therefore, in this review, we summarize the current advances in SARS-CoV-2 knowledges, in light of pre-existing information of other recently emerging coronaviruses. We depict the specificity of the immune response of wild bats and discuss current knowledge of the genetic diversity of bat-hosted coronaviruses that promotes viral genome expansion (accessory gene acquisition). In addition, we describe the basic virology of coronaviruses with a special focus SARS-CoV-2. Finally, we highlight, in detail, the current knowledge of genes and accessory proteins which we postulate to be the major keys to promote virus adaptation to specific hosts (bat and human), to contribute to the suppression of immune responses, as well as to pathogenicity.

Keywords: SARS-CoV-2; accessory proteins; biology; evolution; origin.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The genomes of alpha-CoVs (HCoV-229E, HCoV-NL63), beta-Covs (MHV, HCoV-OC43, HCoV-HKU1, Bat-SL-RaTG13, SARS-CoV-1, MERS-CoV and SARS-CoV-2), delta-Covs (IBV), and gamma-CoVs (PDCoV). Coronaviruses contain a positive-sense, single-stranded RNA [ssRNA (+)] genome of 27–32 kb. The 5′-terminal two thirds of the genome encode a polyprotein pp1a and pp1b which are further cleaved into 16 nps that are involved in genome transcription and replication. The 3′ terminus encodes structural proteins: envelope glycoprotein (S), envelope (E), membrane (M), and nucleocapsid (N). In addition, accessory genes species-specific are interspersed or embedded as an alternative ORF within another genes (the ORF I gene of MHV, the Ia and Ib gene). The SARS-CoV-1 (SARS-CoV-1 reference sequence AY274119) possess 9 ORFs (ORF3a, 3b, 6, 7a, 7b, 8a, 8b, 9b, and 9c), the MERS (MERS-CoV reference sequence NC_019843) retains 6 ORFS (ORF3, 4a, 4b, 5, 8b, and 8c), and the SARS-CoV-2 (SARS-CoV-2 reference sequence NC_045512) has 11 ORFS (ORF3a, 3b, 3c, 3d, 6, 7a, 7b, 8, 9b, 9c, and 10).
FIGURE 2
FIGURE 2
Origin and transmission of coronaviruses. Schematic representation of the origin and transmission of coronaviruses, as well as SARS-CoV-2, between hosts and humans (Mahtarin et al., 2020).
FIGURE 3
FIGURE 3
(A) Schematic representation of the SARS-CoV-2 virus structure. Together with membrane (M), envelope (E) transmembrane proteins, the spike (S) glycoprotein projects from a host cell-derived lipid bilayer. The positive-sense viral genomic RNA is associated with the nucleocapsid proteins forming the ribonucleoprotein (Mandala et al., 2020; Yao et al., 2020; Zhao et al., 2020). (B) The coronavirus life cycle. The coronavirus binds to the specific receptor (for SARS-CoV-2 the ACE2) together with the host factor TMPRSS2. Following entry, from the viral genomic RNA a translation of the two large open reading frames (ORF1a and ORF1b) occur. The resulting polyproteins are processed into individual non-structural proteins (16nsps) that form the replication and transcription complex (RTC). Formation of nuclear double membrane spherules (DMVs) associated with RTC allows viral genomic RNA replication and transcription of subgenomic mRNAs (sg mRNA). Produced structural proteins translocate into endoplasmic reticulum (ER) membranes and transit through the ER to the Golgi intermediate compartment (ERGIC) where nucleocapsid proteins (N) interact with newly produced genomic RNA resulting in the budding into the lumen of vesicular compartments. Finally, virions are secreted by exocytosis from the infected cell.
FIGURE 4
FIGURE 4
Amino acid alignment of ORFs encoding accessory proteins. (A) Amino acid alignment of ORF3a and 3b sequences of SARS-CoV-1 (AY274119), Bat-SL-CoV-Rp3 (DQ071615), SARS-CoV-2 (NC_045512), Bat-SL-CoV-RaTG13 (MN996532), Bat-SL-CoV-RmYN02 (JX993988), Pangolin-CoV-2019 (MT121216). No ORF3b is found in the Bat-SL-CoV-RmYN02 and Pangolin-CoV-2019 sequences, the stars indicate the stop codons. Amino acid alignment of ORF3c and 3d sequences. ORF3d is only found in the SARS-CoV-2. The asterisks indicate the stop codons. (B) Amino acid alignment of ORF6, 7a and 7b sequences. (C) Amino acid alignment of ORF8, 9b, 9c, and 10 sequences. The SARS-CoV-1 ORF8 went through a gradual deletion over the course of the epidemic and at the end of the outbreak ORF8 was divided in 2 ORFS (ORF8a and 8b). ORF10 is only found in SARS-CoV-2, Bat-SL-CoV-RaTG13 and Pangolin-CoV-2019. Sequences were analyzed using Unipro UGENE: a unified bioinformatics tollkit Okonechnikov; Golosova; Fursov. Bioinformatics 2012 28: 1,166–1,167. Amino-acids are color-coded according Clustal X. For each ORF, the SARS-CoV-2 sequence (NC_045512) was used as a reference sequence to perform the alignment.
FIGURE 5
FIGURE 5
Expression of the ORF accessory genes embedded in the N gene. (A) AlphaCoV. HCoV-NL63 (AY567487), the initiation of the ORFN represented an optimal Kozak context (A at –3, G at +4). The initiation of the ORFIa indicated a suboptimal Kozak context (C at –3, A at +4). The initiation of the ORFIb represented a suboptimal Kozak context (C at –3, G at +4) (281). The initiation of the ORFIc indicated a suboptimal Kozak context (A at –3, U at +4). HCoV-229E (AF304460), the initiation of the ORFN represented an optimal Kozak context (A at –3, G at +4). The initiation of the ORFIa indicated a suboptimal Kozak context (G at –3, U at +4). Even if a start codon is presented at the same site as the start codon of ORF9b of SARS-CoV-1 or SARS-CoV-2, a stop codon (asterisk) is found on the third codon following the start codon. The initiation of the ORFIb represented a suboptimal Kozak context (U at –3, U at +4). BetaCoVs. HCoV-OC43 (AY903460), the initiation of the ORFN represented an optimal Kozak context (A at –3, G at +4). The initiation of the ORFI indicated a suboptimal Kozak context (A at –3, U at +4). HCoV-HKU1 (AY597011), the initiation of the ORFN represented a suboptimal Kozak context (A at –3, U at +4). The initiation of the ORFI indicated a suboptimal Kozak context (A at –3, C at +4). (B) BetaCoVs. SARS-CoV-1 and Bat-SL-CoV-Rp3, the initiation of the ORFN represented a suboptimal Kozak context (A at –3, U at +4). The initiation of the ORF9b indicated an optimal Kozak context (A at –3, G at +4). The start codon for ORF9b is very close to the start codon for ORFN (only 10 nucleotides between the ATG of N and the ATG of OR9b). The initiation of the ORF9c represented a suboptimal Kozak context (A at –3, C at +4). SARS-CoV-2, Bat-SL-CoV-RaTG13, Bat-SL-CoV-RmYN02 and Pangolin-CoV-2019, the initiation of the ORFN represented a suboptimal Kozak context (A at –3, U at +4). The initiation of the ORF9b indicated an optimal Kozak context (A at –3, G at +4). The start codon for ORF9b is very close to the start codon for ORFN (only 10 nucleotides between the ATG of N and the ATG of OR9b). The initiation of the ORF9c represented a suboptimal Kozak context (A at –3, C at +4).
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