Difference between revisions of "deLemus"

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__NOTOC__
 
__NOTOC__
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Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoprotein
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''Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoproteins''
  
 +
</br>
 +
The dynamic epidemiology of coronavirus disease 2019 (COVID-19) since its outbreak has been a result of the continuous evolution of its etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), namely alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2), together with numerous variants of interest (VOI). The latest lineage to be designated a VOC would be omicron (B.1.1.529),<ref name="Karim" /> from which a diverse variant soup is generated.<ref>Callaway, E. COVID ‘variant soup’ is making winter surges hard to predict. ''Nature'' '''611,''' 213 (2022).</ref> From the original BA.1 strain of November 2021 to the most recent XBB and BQ.1 strains of late 2022,<ref name="Wang" /><ref name="European Centre" /> each omicron subvariant has successively proliferated and outcompeted its once dominant antecedent.<ref name="Del Rio" /> The emergence of all these variants has brought along many novel mutations that continue to fine-tune the fitness of the virus,<ref>Carabelli, A. M. ''et al.'' SARS-CoV-2 variant biology: Immune escape, transmission and fitness. ''Nat Rev Microbiol'' (2023). DOI: https://doi.org/10.1038/s41579-022-00841-7.</ref><ref>Witte, L. ''et al.'' Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape. ''Nat Commun'' '''14,''' 302 (2023).</ref> leading to its persistent global circulation. Recent emerging variant (EV) data retrieved from GISAID, as of 17 January 2023, has revealed that the top 4 most rapidly spreading lineages are the BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1 variants, among which XBB.1.5 has been found to be especially prevalent in the US,<ref>Callaway, E. Coronavirus variant XBB.1.5 rises in the United States — is it a global threat? ''Nature'' '''613,''' 222 (2023).</ref> making up of more than 40% of its sequence coverage in early January 2023.
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==Spike Glycoprotein==
 
==Spike Glycoprotein==
−
The spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a trimeric type I viral fusion protein that binds the virus to the angiotensin-converting enzyme 2 (ACE2) receptor of a host cell.<ref>Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. ''Nat Rev Mol Cell Biol'' '''23,''' 3–20 (2021).</ref> It is composed of 2 subunits: the N-terminal subunit 1 (S1) and C-terminal subunit 2 (S2), within which multiple domains lie. The S1 region facilitates ACE2 binding and is made up of an N-terminal domain (NTD ~ 1 – 325), a receptor-binding domain (RBD ~ 326 – 525), and 2 C-terminal subdomains (CTD1 and CTD2 ~ 526 – 688), while the downstream S2 region is responsible for mediating virus-host cell membrane fusion.
+
The spike glycoprotein of SARS-CoV-2 is a trimeric type I viral fusion protein that binds the virus to the angiotensin-converting enzyme 2 (ACE2) receptor of a host cell.<ref name="Jackson2021"/> It is composed of 2 subunits: the N-terminal subunit 1 (S1) and C-terminal subunit 2 (S2), within which multiple domains lie. The S1 region facilitates ACE2 binding and is made up of an N-terminal domain (NTD), a receptor-binding domain (RBD), and 2 C-terminal subdomains (CTD1 and CTD2), while the downstream S2 region is responsible for mediating virus-host cell membrane fusion.
  
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=='''Update'''==
 +
The identified leading mutations in 2023 are listed as follows <ref name="deLemus" />:
  
−
='''<big>Update (03/02/2023)</big>'''=
+
<tabs>
−
<big>A recently discovered omicron sublineage known as XBB.1.5 has been spreading rampantly in the US since late December 2022.<ref name="COVID Data Tracker"/>
 
−
Even though this new variant harbors only a single novel mutation, F486P, its hACE2-binding affinity has been significantly increased to a level of up to five folds when compared to its ancestor, XBB.1.<ref name="XBB.1.5"/> The figures in the sections below summarize the mutations carried by various emerging variants, juxtaposed with our detected leading mutations. As depicted, our method has successfully reported the crucial F486P mutation that defines the XBB.1.5 strain. In fact, our method has outlined this specific mutation since as early as November 2022.</big>
 
  
−
<big>Other mutations that were outlined by our deLemus analysis in December 2022, and were subsequently identified as new emerging mutations carried by the top 4 most rapidly spreading lineages according to the latest data retrieved from GISAID (2023.01.25), are listed as follows:</big>
+
<tab name="2023.12">
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<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-12.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
  
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<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/ConfirmedTable.png" alt="test for htmltag img" class="wikimg" style="display: block;width:40%;margin-left: auto;margin-right: auto;"></htmltag>
+
===2023.12.01-2023.12.17===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:burlywood;">'''L455F'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:burlywood;">'''A475V'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:hotpink;">'''E654K'''</span> || HK.3
 +
|}
  
−
==Outlined Leading Mutations==
+
</tab>
  
−
<big>Based on recent report of emerging mutation from GISAID (2023.02.03), deLemus confirmed the following mutation:</big>
+
<tab name="2023.11">
−
===V445A===
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<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-11.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
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<big>The V445A mutation (BQ.1.1) outlined by our deLemus analysis is located at an RBD epitope targeted by several antibodies.<ref name="Weisblum_eLife"/> This mutation has been experimentally shown to not only diminish the neutralization activity of the antibody LY-CoV1404 (bebtelovimab) that is highly potent against most VOCs, including the previously circulating omicron subvariants BA.1.1.59 and BA.2, but also reduce ACE2 competition.<ref name="CellRep20220517"/><br /></big>
 
  
 +
===2023.11.01-2023.11.17===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''N185D'''</span> || HK.3.2
 +
|-
 +
| <span style="color:burlywood;">'''L455F'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:burlywood;">'''A475V'''</span> || JF.1
 +
|-
 +
| <span style="color:hotpink;">'''T572I'''</span> || FY.2
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> || XBB.1.16
 +
|-
 +
| <span style="color:cornflowerblue;">'''D1153Y'''</span> || HK.3
 +
|}
  
 +
</tab>
  
−
<big>The following leading mutations call for special attention with respect to the upcoming variants.</big>
+
<tab name="2023.10">
−
=== A27P ===
+
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-10.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
−
<big>The A27P mutation outlined by our deLemus analysis is located at an NTD antigenic site targeted by the group 3 antibody C1717 capable of neutralizing the beta, gamma, and omicron SARS-CoV-2 variants.<ref name=":2">Li, B. et al. Identification of Potential Binding Sites of Sialic Acids on the RBD Domain of SARS-CoV-2 Spike Protein. ''Front Chem.'' '''9''', 659764 (2021)</ref> Substitution of the A27 residue, which has been found to interact with one of C1717’s complementary-determining regions (CDR), CDRH2,<ref name=":2" /> to proline may therefore affect the binding of this antibody.</big>
+
 
 +
===2023.10.06===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:burlywood;">'''L455F'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:burlywood;">'''A475V'''</span> || GK.1
 +
|}
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.09">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-09.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
 +
 
 +
===2023.09.08-2023.09.28===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:burlywood;">'''R403K'''</span> || BA.2.86 (Pirola)
 +
|-
 +
| <span style="color:burlywood;">'''L455F'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:burlywood;">'''S494P'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:burlywood;">'''P521S'''</span> || XBB.1.16.15
 +
|-
 +
| <span style="color:hotpink;">'''E554K'''</span> || BA.2.86 (Pirola) & FE.1
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> || BA.2.86 (Pirola)
 +
|-
 +
| <span style="color:hotpink;">'''P621S'''</span> || BA.2.86 (Pirola)
 +
|-
 +
| <span style="color:cornflowerblue;">'''T732I'''</span> || XBB.2.3 x XBB.1.5
 +
|-
 +
| <span style="color:cornflowerblue;">'''S939F'''</span> || BA.2.86 (Pirola)
 +
|-
 +
| <span style="color:cornflowerblue;">'''V1264L'''</span> || CK.1.1
 +
|}
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.08">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-08.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
 +
 
 +
<big>Here are the recently confirmed leading mutations.</big>
 +
 
 +
===2023.08.04 - 2023.08.22===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''N185D'''</span> || XBB.1.5
 +
|-
 +
| <span style="color:yellowgreen;">'''L212S'''</span> || FY.4.2
 +
|-
 +
| <span style="color:burlywood;">'''V445A'''</span> || XBC.1.6
 +
|-
 +
| <span style="color:burlywood;">'''L455F'''</span> || EG.5.1.1
 +
|-
 +
| <span style="color:burlywood;">'''F456L'''</span> || EG.5.1 (Eris)
 +
|-
 +
| <span style="color:hotpink;">'''E554Q'''</span> || XBB.1.5.18
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> || XBB.1.16
 +
|-
 +
| <span style="color:cornflowerblue;">'''T883I'''</span> || XBB.1.16
 +
|}
 +
''*The reported mutations of detected variants are from Cov-Lineages<ref name="Cov-Lineages" />''
 +
</br>
 +
===<big>RBD Mutation Profile of Latest VOIs.</big>===
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-08_VarRBD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:65%;margin-left: auto;margin-right: auto;"></htmltag>
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.07">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-07.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
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 +
* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
 +
 
 +
<big>Here are the recently confirmed leading mutations.</big>
 +
 
 +
===2023.06.30 - 2023.07.05===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''H146K'''</span> || FL.2.3 (XBB.1.9.1.2.3)
 +
|-
 +
| <span style="color:burlywood;">'''S446N'''</span> || FL.19
 +
|-
 +
| <span style="color:burlywood;">'''F456L'''</span> || XBF
 +
|}
 +
 
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.06">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-06.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
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* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
 +
 
 +
<big>Here are the recently confirmed leading mutations.</big>
 +
 
 +
===2023.06.01 - 2023.06.13===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:burlywood;">'''F490P'''</span> || XBB.1.9.1
 +
|-
 +
| <span style="color:hotpink;">'''E554K'''</span> || XBB.1.9.1 (sublineage)
 +
|-
 +
| <span style="color:hotpink;">'''Q675K'''</span> || XBB.1.22.1
 +
|-
 +
| <span style="color:cornflowerblue;">'''L858I'''</span> || CH.1.1.1
 +
|}
 +
 
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.05">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-05.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
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 +
* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
 +
 
 +
<big>Here are the recently confirmed leading mutations.</big>
 +
 
 +
===2023.05.01 - 2023.05.12===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:burlywood;">'''F456L'''</span> || FD.1.1 & EG.5.1 (2023.08)
 +
|-
 +
| <span style="color:burlywood;">'''S494P'''</span> || XBB.2.3 & XBB.1.1
 +
|-
 +
| <span style="color:hotpink;">'''T572I'''</span> || FY.1 ( XBB.1.22.1.1 )
 +
|}
 +
''*The reported mutations of detected variants are from GISAID''
 +
 
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.04">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-04.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
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 +
* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
 +
 
 +
<big>Here are the recently confirmed leading mutations.</big>
 +
 
 +
===2023.04.01 - 2023.04.21===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''H146K'''</span> || XBB.1.5 & XBB.1.16
 +
|-
 +
| <span style="color:yellowgreen;">'''M153I'''</span> || XBB.2.3.3
 +
|-
 +
| <span style="color:yellowgreen;">'''E180V'''</span> || XBB.1.16
 +
|-
 +
| <span style="color:burlywood;">'''K444R'''</span> || XBB.1.5
 +
|-
 +
| <span style="color:burlywood;">'''T478R'''</span> || XBB.1.16, XBB.1.5, CH.1.1.2 & XBB.2.3
 +
|-
 +
| <span style="color:burlywood;">'''F490P'''</span> || XBB.2.6
 +
|-
 +
| <span style="color:burlywood;">'''S494P'''</span> || XBB.1.5
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> || XBB.1.16
 +
|-
 +
| <span style="color:hotpink;">'''P621S'''</span> || XBB.2.3
 +
|-
 +
| <span style="color:hotpink;">'''A688V'''</span> || XAY.1.1.1
 +
|}
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.03">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-03.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
 +
<html>
 +
    <style>
 +
        .molstar {
 +
            position: relative;
 +
            width: 80%;
 +
            padding-bottom: 56.25%;
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 +
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 +
    <link rel="stylesheet" type="text/css" href="https://molstar.org/viewer/molstar.css" />
 +
    <script type="text/javascript" src="https://molstar.org/viewer/molstar.js"></script>
 +
 
 +
    <div id="viewer-3" class="molstar" style="display: block; margin-left:auto; margin-right:auto; padding-bottom: 40%;"></div>
 +
    <script type="text/javascript">
 +
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 +
</html>
 +
* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
 +
 
 +
<big>Here are the recently confirmed leading mutations.</big>
 +
 
 +
===2023.03.01 - 2023.03.21===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''Y248S'''</span> || BQ.1
 +
|-
 +
| <span style="color:burlywood;">'''F490P'''</span> || XBB.1 & XBB.1.5
 +
|-
 +
| <span style="color:hotpink;">'''T547I'''</span> || XBB.1.16
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> || DV.1, CH.1.1.1 & CH.1.1.17
 +
|-
 +
| <span style="color:hotpink;">'''I666V'''</span> || XBB.1.5
 +
|-
 +
| <span style="color:cornflowerblue;">'''V1264L'''</span> || CH.1.1
 +
|}
 +
 
 +
</tab>
 +
 
 +
<tab name="2023.02">
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-02.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
 +
<html>
 +
    <style>
 +
        .molstar {
 +
            position: relative;
 +
            width: 80%;
 +
            padding-bottom: 56.25%;
 +
        }
 +
    </style>
 +
    <link rel="stylesheet" type="text/css" href="https://molstar.org/viewer/molstar.css" />
 +
    <script type="text/javascript" src="https://molstar.org/viewer/molstar.js"></script>
  
−
=== K147- ===
+
    <div id="viewer-2" class="molstar" style="display: block; margin-left:auto; margin-right:auto; padding-bottom: 40%;"></div>
−
<big>The K147- mutation outlined by our deLemus analysis is located at the NTD. Molecular dynamics studies have shown that the K147 residue is involved in interacting with multiple monoclonal antibodies,<ref name=":4">Zhou, L, ''et al''. Predicting Spike Protein NTD Mutations of SARS-CoV-2 Causing Immune Evasion by Molecular Dynamics Simulations. ''Phys Chem Chem Phys '''''24''', 3410–3419 (2022).</ref></big> <big>whose mutation to threonine, K147T, has been experimentally found to promote immune evasion.<ref name=":3">McCallum, M. ''et al''. N-Terminal Domain Antigenic Mapping Reveals a Site of Vulnerability for SARS-CoV-2. ''Cell'' '''184''', 2332-2347 (2021).</ref></big> <big>It is therefore likely that a deletion at this position may affect the binding of antibodies, thereby reducing the neutralization susceptibility of the virus.</big>
+
    <script type="text/javascript">
 +
        molstar.Viewer.create('viewer-2', {
 +
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 +
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 +
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 +
            layoutShowLeftPanel: true,
  
−
=== Q183G ===
+
            viewportShowExpand: true,
−
<big>The Q183G mutation outlined by our deLemus analysis is located at an NTD sialoside-binding site,<ref>Guo, H. ''et al''. The Glycan-Binding Trait of the Sarbecovirus Spike N-Terminal Domain Reveals an Evolutionary Footprint. ''J Virol.'' '''96''', e00958-22 (2022)</ref> whose interactions with anionic glycoconjugates of the cell surface mediate the viral attachment.<ref>Sun, X.-L. The role of cell surface sialic acids for SARS-CoV-2 infection. ''Glycobiology'' '''31,''' 1245–1253 (2021).</ref> The loss of an amide group due to the glutamine-to-glycine substitution may abrogate hydrogen bond formation between amino acid site 183 and the carboxylic group of surface sialosides,<ref>Buchanan, C. J. ''et al.'' Pathogen-sugar interactions revealed by Universal Saturation Transfer Analysis. ''Science'' '''377,''' (2022).</ref> thereby altering the cell entry efficiency of SARS-CoV-2.</big>
+
            viewportShowSelectionMode: false,
 +
            viewportShowAnimation: false,
 +
        }).then(viewer => {
 +
            viewer.loadSnapshotFromUrl('https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/pdb/LM_2023_02.molx', 'molx');
 +
        });
 +
    </script>
 +
</html>
 +
* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
  
−
=== H245N ===
+
<big>Here are the recently confirmed leading mutations.</big>
−
<big>The H245N mutation outlined by our deLemus analysis is located in the supersite loop of the NTD antigenic supersite, where 2 antibodies in particular, SLS28 and S2X333, bind.<ref name=":4" /><ref name=":3" /> The loss of a positive charge resulted from the replacement of a cationic histidine residue is speculated to alter the neutralization resistance of the spike glycoprotein. Furthermore, it has been noticed that the histidine-to-asparagine substitution introduces a novel NXS sequon (<sub>245</sub>NRS<sub>247</sub>), which may potentially be ''N''-glycosylated.</big>
 
  
−
=== G257D ===
+
===2023.02.03 - 2023.02.20===
−
<big>The G257D mutation outlined by our deLemus analysis is located in the supersite loop of the NTD antigenic supersite, where 2 antibodies in particular, SLS28 and S2X333, bind.<ref name=":4" /><ref name=":3" /> The gain of a negative charge resulted from the introduction of an anionic aspartic acid residue is speculated to alter the neutralization resistance of the spike glycoprotein.</big>
+
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''K147I'''</span> || XBB.1.5.2.1
 +
|-
 +
| <span style="color:yellowgreen;">'''Y248S'''</span> || BQ.1.1.43
 +
|-
 +
| <span style="color:burlywood;">'''S494P'''</span> || XBB.1.5
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> || XBB.1.9.2 & XBB.2.4
 +
|-
 +
| <span style="color:hotpink;">'''P612S'''</span> || XBF
 +
|-
 +
| <span style="color:hotpink;">'''T678I'''</span> || BA.2.75 x BA.5
 +
|-
 +
| <span style="color:hotpink;">'''N679R'''</span> || CH.1.1
 +
|-
 +
| <span style="color:cornflowerblue;">'''P1162S'''</span> || XBK.1
 +
|}
 +
''*The reported mutations of detected variants are from GISAID<ref name="GISAID" />''
 +
</tab>
  
−
=== A262S ===
+
<tab name="2023.01">
−
<big>The A262S mutation outlined by our deLemus analysis is located at the NTD. This mutation has been experimentally shown to enhance the utilization of ACE2 in numerous mammals, including humans,<ref>Wang, Q. ''et al''. Key Mutations on Spike Protein Altering ACE2 Receptor Utilization and Potentially Expanding Host Range of Emerging SARS‐CoV‐2 Variants. ''J Med Virol.'' '''95''', 1-11 (2022).</ref> indicating that variants carrying this alanine-to-serine substitution may possess increased interspecies and intraspecies transmissibility.</big>
+
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/2023-01.png" alt="test for htmltag img" class="wikimg" style="display: block;width:100%;margin-left: auto;margin-right: auto;"></htmltag>
  
−
===R346I/S ===
+
<html>
−
<big>The R346I/S mutation outlined by our deLemus analysis is located at an RBD epitome to which multiple class 3 antibodies bind.<ref>Gaebler, C. ''et al.'' Evolution of antibody immunity to SARS-CoV-2. ''Nature'' '''591,''' 639–644 (2021).</ref> Structural analyses have revealed that this arginine-to-isoleucine/serine change weakens the intermolecular interactions between amino acid 346 and several class 3 antibodies, enabling virions bearing this mutation to possess enhanced immune evasion capabilities.<ref>Wang, Q. ''et al.'' Resistance of SARS-CoV-2 omicron subvariant BA.4.6 to antibody neutralisation. ''Lancet Infect Dis'' '''22,''' 1666–1668 (2022).</ref> In fact, experimental studies have demonstrated that R346S in particular can promote neutralization resistance of viruses without comprising their ACE2-binding affinity</big>.<big><ref>Yi, C. ''et al.'' Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants. ''Genome Med'' '''13,''' (2021).</ref><ref>Magnus, C. L. ''et al.'' Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab. ''Front Immunol'' '''13,''' (2022).</ref></big><br />
+
    <style>
 +
        .molstar {
 +
            position: relative;
 +
            width: 80%;
 +
            padding-bottom: 56.25%;
 +
        }
 +
    </style>
 +
    <link rel="stylesheet" type="text/css" href="https://molstar.org/viewer/molstar.css" />
 +
    <script type="text/javascript" src="https://molstar.org/viewer/molstar.js"></script>
  
−
===N450D===
+
    <div id="viewer-1" class="molstar" style="display: block; margin-left:auto; margin-right:auto; padding-bottom: 40%;"></div>
−
<big>The N450D mutation outlined by our deLemus analysis is located at the RBD β-sheet 1 region which has been shown to reinforce the spike-ACE2 binding in silico.<ref>Cong, Y. ''et al.'' Anchor-locker binding mechanism of the coronavirus spike protein to human ACE2: Insights from computational analysis. ''J Chem Inf Model'' '''61,''' 3529–3542 (2021).</ref></big> <big>The possible effects of this mutation have yet to be studied, but it has been speculated that the substitution of an electrically neutral asparagine residue to an anionic aspartic acid residue may disfavor virus-receptor attachment, owing to the overall negative charge of the ACE2 binding surface.<ref>Xie, Y. ''et al.'' Spike proteins of SARS-CoV and SARS-CoV-2 utilize different mechanisms to bind with human ACE2. ''Front Mol Biosci'' '''7,''' (2020).</ref></big><br />
+
    <script type="text/javascript">
 +
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 +
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 +
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 +
            layoutShowSequence: true,
 +
            layoutShowLog: false,
 +
            layoutShowLeftPanel: true,
  
−
===E484R/S===
+
            viewportShowExpand: true,
−
<big>The E484R/S mutation outlined by our deLemus method is located within the receptor binding motif (RBM) of the RBD. Recognized by ACE2 and multiple neutralizing antibodies,<ref name=":1">Gan, H. H., Twaddle, A., Marchand, B. & Gunsalus, K. C. Structural modeling of the SARS-CoV-2 spike/human ACE2 complex interface can identify high-affinity variants associated with increased transmissibility. ''J Mol Biol'' '''433,''' 167051 (2021).</ref> immense selection pressure exerted on this amino acid site has generated a high degree of polymorphism for residue 484, as seen from the fact that most SARS-CoV-2 variants carry substitutions in this site, encompassing the E484K of beta, gamma, and eta (B.1.525), E484Q of kappa (B.1.617.1), and E484A of omicron. All these mutations confer immune escape effects,<ref name=":0">Harvey, W. T. ''et al.'' SARS-CoV-2 variants, Spike mutations and immune escape. ''Nat Rev Microbiol'' '''19,''' 409–424 (2021).</ref><ref>Liu, Z. ''et al.'' Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. ''Cell Host Microbe'' '''29,''' (2021).</ref><ref name="VanBlargan2022" /> where the 2 former ones in particular can additionally strengthen the ACE2-binding affinity of the virus.<ref name=":1" /> Similarly, E484R, which also replaces the initially anionic aspartic acid residue with a cationic one, has been shown to promote both immune evasion and ACE2-binding.<ref name=":1" /> The function of E484S, on the other hand, have yet to be deduced.<br /></big>
+
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 +
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 +
        });
 +
    </script>
 +
</html>
 +
* Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).
  
−
=== D574V ===
+
<big>Here are the recently confirmed leading mutations.</big>
−
<big>The D574V mutation outlined by our deLemus analysis is located at the CTD1 region. Since the aspartic acid residue of amino acid site 574 is capable of interacting with the pH-dependent S2 refolding domain responsible for regulating RBD up-down motion, its substitution to an electrically neutral valine residue may alter the endosomal entry efficiency and immune evasion ability of SARS-CoV-2.<ref>Zhou, T. ''et al.'' Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains. ''Cell Host Microbe'' '''28,''' (2020).</ref></big>
 
  
−
===P681Y===
+
===2023.01.31===
−
<big>The P681Y mutation outlined by our deLemus analysis is located at the C-terminal of the CTD2, which contains the S1/S2 furin cleavage site (<sub>681</sub>PRRAR↓S<sub>686</sub>) important for viral transmission.<ref>Jaimes, J. A., Millet, J. K. & Whittaker, G. R. Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 Site. ''iScience'' '''23,''' 101212 (2020).</ref><ref>Hoffmann, M., Kleine-Weber, H. & Pöhlmann, S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. ''Mol Cell'' '''78,''' (2020).</ref> This amino acid site is particularly polymorphic, as demonstrated by the fact that multiple existing variants carry divergent mutations at this site, being the P681H of alpha and omicron and P681R of delta and kappa. Interestingly, this substitution is speculated to diminish the cleavage efficiency of the S1/S2 interface because the bulky nature of tyrosine hinders the binding of furin to the cleavage loop.<ref>Henrich, S. ''et al.'' The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. ''Nat Struct Mol Biol'' '''10,''' 520–526 (2003).</ref><ref>Tian, S. A 20 residues motif delineates the furin cleavage site and its physical properties may influence viral fusion. ''Biochem Insights'' '''2,''' (2009).</ref></big>
+
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:burlywood;">'''V445A'''</span> || BQ.1.1
 +
|-
 +
| <span style="color:cornflowerblue;">'''T883I'''</span> || BQ.1.1
 +
|}
 +
===2023.01.17 - 2023.01.25===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants
 +
|-
 +
| <span style="color:yellowgreen;">'''H146- / H146K'''</span> || BQ.1.1 / XBB.1.5
 +
|-
 +
| <span style="color:burlywood;">'''F486A'''</span> || BQ.1.1
 +
|-
 +
| <span style="color:hotpink;">'''E583D'''</span> || BQ.1.1
 +
|-
 +
| <span style="color:hotpink;">'''Q613H'''</span> ||  BQ.1.1
 +
|-
 +
| <span style="color:cornflowerblue;">'''S939F'''</span> || BQ.1.1
 +
|}
  
−
=== D796H ===
+
</tab>
−
<big>The D796H mutation outlined by our deLemus analysis is located in the S2 region. A study has shown that the administration of convalescent plasma therapy to a chronic infection patient prompted the emergence of this mutation, together with deletions spanning the NTD sites 69 and 70 (H69/V70-), within the patient's viral population.<ref name="KempCIP" /> The single aspartic acid-to-histidine substitution was found to enhance the neutralization resistance of the spike glycoprotein at the cost of lowering its infectivity, an undesirable effect that can be compensated by the H69/V70- double deletion.<ref name="KempCIP" /></big>
 
  
−
==Summary==
+
</tabs>
−
<big>The constantly shifting epidemiology of coronavirus disease 2019 (COVID-19) ever since its initial outbreak has been a result of the continuous evolution of its etiological agent, SARS-CoV-2, from which numerous variants have been generated. Even within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), which are the previously circulating alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2) strains, and many other variants of interest (VOI). The successive emergence of new SARS-CoV-2 variants has brought along many novel mutations, most of which continually refine and improve the fitness of the virus. For instance, these functionally advantageous mutations include the N501Y of alpha and L452R and E484Q of the B.1.617 lineage, which are capable of enhancing the ACE2-binding affinity of the spike glycoprotein.<ref>Aggarwal, A. ''et al''. Mechanistic Insights into the Effects of Key Mutations on SARS-CoV-2 RBD–ACE2 Binding. ''Phys Chem Chem Phys'' '''23''',  26451–26458 (2021)</ref></big>
 
  
−
<big>The latest SARS-CoV-2 lineage to be designated the status of VOC would be omicron (B.1.1.529) which first originated from South Africa.<ref name="Karim" /> This particular lineage alone has undergone substantial evolution over the course of its global dominance, spreading across the world like wildfire while simultaneously producing a diverse soup of dissimilar subvariants.<ref name="Tegally" /> The first of its kind would be the BA.1 strain first appeared in November 2022. The supremacy of BA.1, however, would not last long, forasmuch as the emergence of the more fit BA.2 strain in December 2022 would eventually outcompete its antecedent.<ref name="Yamasoba" /> Few months later, between March and July 2022, the successive emergences of BA.2.12.1, BA.4 and BA.5, and BA.2.75 would once again garnered the attention of the WHO and multiple countries. For one, the BA.2.12.1, BA.4, and BA.5 subvariants were found to possess enhanced antibody evasion capabilities and transmissibility when compared to the formerly active BA.2 strain,<ref name="Tegally" /><ref>Cao, Y. ''et al.'' BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron Infection. ''Nature'' '''608,''' 593–602 (2022).</ref><ref>Wang, Q. ''et al.'' Antibody evasion by SARS-CoV-2 omicron subvariants BA.2.12.1, BA.4 and BA.5. ''Nature'' '''608,''' 603–608 (2022).</ref> allowing them to become dominant in the US and the UK.<ref name="Callaway" /><ref name="Del Rio" /></big> <big>BA.2.75, on the other hand, was the dominant variant in India, which habors higher hACE2-binding affinity than the BA.4 and BA.5 subvariants.<ref>Cao, Y. ''et al.'' Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75. ''Cell Host Microbe'' '''30,''' (2022).</ref><ref name="Shaheen" /> The complex interactions between these omicron sublineages prompted the creations of even more novel strains, including the recombinant XBB subvariant derived from BA.2.10.1 and BA.2.75 in August 2022, and the BQ.1 subvariant derived from BA.5 in October 2022. Like their predecessors, XBB swiftly rose to prominence upon its emergence, which was then succeeded by BQ.1 up till the end of 2022.<ref name="Wang" /><ref name="European Centre" />
 
−
In fact, BQ.1.1, a descendent of BQ.1, was found to be the culprit behind 36.3% of the total US reported COVID-19 cases in December 2022.<ref name="CNBC XBB.1.5" /></big>
 
  
−
<big>Recent emerging variant (EV) data retrieved from GISAID, as of 17 January 2023, has revealed that the top 4 most rapidly spreading lineages are the BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1 variants, among which XBB.1.5 has been found to be especially prevalent in the US, making up of more than 40% of its sequence coverage in early January 2023.<ref name="CNBC XBB.1.5" /> The identified leading mutations are listed as follows:
+
<!--
−
<br /></big>
+
===2023.01.31===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants !! Conformation
 +
|-
 +
| V445A || BQ.1.1 || Amino acid site located at an RBD epitope<ref name="Weisblum_eLife"/> ; Mutation reduces neutralization by antibody <ref name="CellRep20220517"/>
 +
|}
 +
===2023.01.17 - 2023.01.25===
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Confirmed in VOC/Emerging Variants !! Conformation
 +
|-
 +
| H146-/K || BQ.1.1, XBB.1.5 || Amino acid site recognized by mAbs targeting NTD<ref name=":3"/>
 +
|-
 +
| E583D || BQ.1.1 || Viral functions to be confirmed by further investigation
 +
|-
 +
| Q613H ||  BQ.1.1 || Speculate to enhance replicative fitness and transmissibility due to close proximity to D614G ; Potential functions to be elucidated<ref name=":0"/><ref name="Bugembe"/>
 +
|-
 +
| S939F || BQ.1.1 || Destabilize both pre-fusion and post-fusion S2 conformation<ref name="Olivie"/> ; Capable to enhance infectivity and modulate T-cell immune response when combined with D614G<ref name="LiImpactCell"/><ref name="Donzelli"/>
 +
|}
  
 +
<big>The following leading mutations call for special attention with respect to the upcoming variants.</big>
 
==NTD==
 
==NTD==
−
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/NTD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
+
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Conformation
 +
|-
 +
| A27P || An antigenic site targeted by the group 3 antibody C1717<ref name=":2" />
 +
|-
 +
| K147- || Involved in interacting with multiple monoclonal antibodies<ref name=":4" /> ; Mutation to threonine (K147T) at this site promotes immune evasion<ref name=":3" />
 +
|-
 +
| N164K || Functional impact to be confirmed in future investigation.
 +
|-
 +
| Q183G || Interactions with surface glycoconjugates mediate the viral attachment<ref name="Sun_Glycobio2021" /> ; Caused a loss of an amide group; May abrogate the hydrogen bond between the amino acid and the carboxylic group of surface sialosides<ref name="Buchanan" />
 +
|-
 +
| N185D || Functional impact to be confirmed in future investigation.
 +
|-
 +
|H245N
 +
|Located in the supersite loop of the NTD antigenic supersite for antibodies SLS28 and S2X333<ref name=":4" /><ref name=":3" /> ; Caused a loss of a positive charge ; Introduces an NXS sequon (<sub>245</sub>NRS<sub>247</sub>) for ''N''-glycosylation
 +
|-
 +
|G252V
 +
|Site is critical for the binding of human antibody COV2-3439<ref>Suryadevara N. ''et al.'' An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer. ''J Clin Invest'' '''132,''' 159062 (2022).</ref>
 +
|-
 +
|G257D
 +
|Located in the supersite loop of the NTD antigenic supersite for antibodies SLS28 and S2X333<ref name=":4" /><ref name=":3" /> ; Caused a gain of negative charge
 +
|-
 +
|A262S
 +
|Enhance the utilization of ACE2 in numerous mammals<ref name="Wang_JMedVirol2022" /> ; May increase interspecies and intraspecies transmissibility
 +
|}
  
 
==RBD==
 
==RBD==
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Conformation
 +
|-
 +
| R346I/S || Possibly lead to immune evasion due to the disruption of class 3 antibodies binding site<ref name="Gaebler"/> <ref name="WangQ_LancetID2022"/>
 +
|-
 +
| K444N/R || Escape mutations for covalescent plasma<ref name="Weisblum_eLife"/>
 +
|-
 +
| G446V || Substantially decreases the neutralization titers of plasma<ref name="Greaney"/>
 +
|-
 +
| N450D || Results in antibody resistance<ref name="Cong_CellHM2021"/>
 +
|-
 +
| E484R/S || A site of mutation being reported in multiple variants, mutation at this site could harbor escape mutations that impede the binding and neutralization ability of antibodies<ref name=":0"/> <ref name="Greaney"/>
 +
|-
 +
| F490P || Mutation at this site enables antibody escape over mAb COV2-2479, COV2-2050, COV2-2096 based on DMS study.<ref name="Greaney"/>
 +
|-
 +
| S494P || This mutation persistently shows up in an immunocompromised patient of COVID-19, which was treated various drugs and antibodies e.g. remdesivir, intravenous immunoglobulin, etc.<ref name="Choi"/>
 +
|}
 +
 +
==CTDs==
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Conformation
 +
|-
 +
| T547I || Functional impact to be confirmed in future investigation.
 +
|-
 +
| T572I || Functional impact to be confirmed in future investigation.
 +
|-
 +
| D574V || Located at the CTD1 region, substitution to an electrically neutral valine residue permits the endosomal entry efficiency and immune evasion ability of SARS-CoV-2.<ref name="Zhou_CellHM2020"/>
 +
|-
 +
| E619Q || Functional impact to be confirmed in future investigation.
 +
|-
 +
| E658S || Functional impact to be confirmed in future investigation.
 +
|-
 +
| I666V || Functional impact to be confirmed in future investigation.
 +
|-
 +
| S673G || Functional impact to be confirmed in future investigation.
 +
|-
 +
| P681Y || Located at the C-terminal of the CTD2, this substitution can diminish the cleavage efficiency of the S1/S2 interface because the bulky nature of tyrosine hinders the binding of furin to the cleavage loop.<ref name="Henrich"/><ref name="Tian_2009"/></big>
 +
|-
 +
| I688V || Functional impact to be confirmed in future investigation.
 +
|}
 +
==S2==
 +
{| class="wikitable"
 +
|-
 +
! Outlined Mutations !! Conformation
 +
|-
 +
| D796H || Located in S2 region, the single aspartic acid-to-histidine substitution was found to enhance the neutralization resistance of the spike glycoprotein in a chronical infection patient.<ref name="KempCIP" /></big>
 +
|}
 +
 +
== References ==
 +
<references>
 +
<ref name="XBB.1.5">Yue, C. ''et al''. Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion. Preprint at https://www.biorxiv.org/content/10.1101/2023.01.03.522427v2 (2023).</ref>
 +
<ref name=":4">Cao, Y. ''et al.'' Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. ''Nature'' (2022). DOI:10.1038/s41586-022-05644-7</ref>
 +
<ref name="Zahradník">Zahradník, J. ''et al.'' SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. ''Nat Microbiol'' '''6,''' 1188 (2021).</ref>
 +
<ref name="Makowski">Makowski, E. K., Schardt, J. S., Smith, M. D. & Tessier, P. M. Mutational analysis of SARS-CoV-2 variants of concern reveals key tradeoffs between receptor affinity and antibody escape. ''PLOS Comput Biol'' '''18,''' (2022).</ref>
 +
<ref name=":0">Qu, P. ''et al.'' Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant. ''Cell Host Microbe'' '''30,''' 1518 (2022).</ref>
 +
<ref name=":2">Tamura, T. ''et al.'' Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two omicron subvariants. Preprint at https://www.biorxiv.org/content/10.1101/2022.12.27.521986v1 (2022).</ref>
 +
<ref name=":3">Wang, Q. ''et al.'' Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. ''Cell'' '''186,''' 279 (2023).</ref>
 +
<ref name=":1">Qu, P. ''et al.'' Enhanced neutralization resistance of SARS-CoV-2 omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. ''Cell Host Microbe'' '''31,''' 9 (2023).</ref>
 +
<ref name="Tuekprakhon">Tuekprakhon, A. ''et al.'' Antibody escape of SARS-CoV-2 omicron BA.4 and BA.5 from Vaccine and BA.1 Serum. ''Cell'' '''185,''' 2422 (2022).</ref>
 +
<ref name="Wang">Wang, Q. ''et al.'' Antibody evasion by SARS-CoV-2 omicron subvariants BA.2.12.1, BA.4 and BA.5. ''Nature'' '''608,''' 603 (2022).</ref>
 +
</references>
 +
 +
==Summary==
 +
<tabs>
 +
<tab name="NTD"><htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/NTD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag></tab>
 +
<tab name="RBD"><htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/RBD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag></tab>
 +
<tab name="CTDs"><htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/CTDs.png" alt="test for htmltag img" class="wikimg" style="display:block;width:70%;margin-left: auto;margin-right: auto;"></htmltag></tab>
 +
<tab name="S2"><htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/S2.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag></tab>
 +
</tabs>
 +
 +
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/NTD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
  
 
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/RBD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
 
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/RBD.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
−
 
−
==CTDs==
 
  
 
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/CTDs.png" alt="test for htmltag img" class="wikimg" style="display:block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
 
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/CTDs.png" alt="test for htmltag img" class="wikimg" style="display:block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
  
−
==S2==
 
 
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/S2.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
 
<htmltag tagname="img" src="https://wiki.laviebay.hkust.edu.hk/deLemus/RESEARCH_TEAMS/images/PublishedPlot/S2.png" alt="test for htmltag img" class="wikimg" style="display: block;width:70%;margin-left: auto;margin-right: auto;"></htmltag>
 +
 +
== '''Deep Mutational Scanning Data''' ==
 +
<big>The RBD-ACE2 binding data</big><ref>Greaney AJ, Starr TN, Gilchuk P, Zost SJ, Binshtein E, Loes AN, Hilton SK, Huddleston J, Eguia R, Crawford KHD, Dingens AS, Nargi RS, Sutton RE, Suryadevara N, Rothlauf PW, Liu Z, Whelan SPJ, Carnahan RH, Crowe JE Jr, Bloom JD. Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition. Cell Host Microbe. 2021 Jan 13;29(1):44-57.e9. doi: 10.1016/j.chom.2020.11.007. Epub 2020 Nov 19. PMID: 33259788; PMCID: PMC7676316.</ref> <big>showed that R346S, N354S, E484R and S494P are the mutations lead to increased binding affinity in all the 5 background sequence.</big>
 +
{| class="wikitable"
 +
|+
 +
RBD-ACE2 binding affinity
 +
|'''Unique  Mutations'''
 +
|'''Date'''
 +
|'''Wuhan'''
 +
|'''Alpha'''
 +
|'''Beta'''
 +
|'''Eta'''
 +
|'''Delta'''
 +
|-
 +
|'''R346S'''
 +
|2023.01
 +
|0.12
 +
|0.14
 +
|0.07
 +
|0.03
 +
|0.11
 +
|-
 +
|'''N354S'''
 +
|2023.05
 +
|0.03
 +
|0.01
 +
|0.04
 +
|0.32
 +
|0.02
 +
|-
 +
|'''E484R'''
 +
|2023.01
 +
|0.06
 +
|0.04
 +
|  -
 +
|  -
 +
|0.11
 +
|-
 +
|'''S494P'''
 +
|2023.01
 +
|0.33
 +
|0.18
 +
|0.13
 +
|0.14
 +
|0.06
 +
|}
 +
<big>Immune escape data</big><ref>Tyler N. Starr., et al., Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution.''Science''377,420-424(2022).DOI:10.1126/science.abo7896</ref> <big>shows that the escape ability of R346S, V445A, G446I, and E484R against certain antibodies exceeds 90% mutations.</big>
 +
{| class="wikitable"
 +
|+
 +
Immune Escaping
 +
|'''Unique  Mutations'''
 +
|'''Date'''
 +
|'''Antybody1'''
 +
|'''Antybody2'''
 +
|'''Antybody3'''
 +
|'''Antybody4'''
 +
|'''Antybody5'''
 +
|-
 +
|'''R346S'''
 +
|2023.01
 +
|COV2-2082
 +
|COV2-2096
 +
|COV2-2479
 +
|COV2-2832
 +
|
 +
|-
 +
|'''V445A'''
 +
|2023.01
 +
|COV2-2050
 +
|COV2-2094
 +
|COV2-2479
 +
|COV2-2499
 +
|COV2-2677
 +
|-
 +
|'''G446I'''
 +
|2023.05
 +
|COV2-2096
 +
|COV2-2479
 +
|COV2-2499
 +
|
 +
|
 +
|-
 +
|'''E484R'''
 +
|2023.01
 +
|COV2-2050
 +
|COV2-2096
 +
|COV2-2479
 +
|COV2-2832
 +
|
 +
|}
 +
<big>Overall, by the first half of this year, '''R346S''' and '''E484R''' are the most potential dangerous mutations we captured.</big>
 +
-->
  
 
==References==
 
==References==
 
<references>
 
<references>
−
<ref name="COVID Data Tracker">COVID Data Tracker: Variant Proportion https://covid.cdc.gov/covid-data-tracker/#variant-proportions (2023).</ref>
+
<ref name="Del Rio">Rössler, A. ''et al''. BA.2 and BA.5 Omicron Differ Immunologically from Both BA.1 Omicron and Pre-Omicron Variants. ''Nat Commun'' '''13''', 7701 (2022)</ref>
−
<ref name="Karim">Karim, S. S. A. & Karim, Q. A. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. ''Lancet'' '''398,''' 2126–2128 (2021).</ref>
+
<ref name="European Centre">Qu, P. ''et al''. Enhanced Neutralization Resistance of SARS-CoV-2 Omicron Subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. ''Cell Host Microbe'' '''31''', 9 (2023)</ref>
−
<ref name="Tegally">Tegally, H. ''et al.'' Emergence of SARS-CoV-2 omicron lineages BA.4 and BA.5 in South Africa. ''Nat Med'' '''28,''' 1785–1790 (2022).</ref>
+
<ref name="Jackson2021">Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. ''Nat Rev Mol Cell Biol'' '''23,''' 3 (2021).</ref>
−
<ref name="Yamasoba">Yamasoba, D. et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. ''Cell'' '''185''', 2103-2115.e19 (2022).</ref>
+
<ref name="Karim">Karim, S. S. A. & Karim, Q. A. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. ''Lancet'' '''398,''' 2126 (2021).</ref>
−
<ref name="Callaway">Callaway, E. What Omicron’s BA.4 and BA.5 variants mean for the pandemic. ''Nature'' '''606''', 848–849 (2022).</ref>
+
<ref name="Wang">Wang, Q. ''et al.'' Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. ''Cell'' '''186,''' 279 (2023).</ref>
−
<ref name="Del Rio">Del Rio, C. & Malani, P. N. COVID-19 in 2022 - The Beginning of the End or the End of the Beginning? ''JAMA'' '''327''', 2389–2390 (2022).</ref>
+
<ref name="deLemus">deLemus team, Analysis of Leading Mutations in SARS-CoV-2 Spike Glycoproteins (in preparation, 2023).</ref>
−
<ref name="Shaheen">Shaheen, N. ''et al.'' Could the New BA.2.75 Sub-Variant Cause the Emergence of a Global Epidemic of COVID-19? A Scoping Review. ''Infect Drug Resist'' '''15,''' 6317–6330 (2022).</ref>
+
<ref name="GISAID">GISAID https://gisaid.org/</ref>
−
<ref name="Wang">Wang, Q. ''et al.'' Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. ''Cell'' '''186,''' (2023).</ref>
+
<ref name="Cov-Lineages">Cov-Lineages https://cov-lineages.org/</ref>
−
<ref name="European Centre">European Centre for Disease Prevention and Control: Spread of the SARS-CoV-2 Omicron variant sub-lineage BQ.1 in the EU/EEA https://www.ecdc.europa.eu/sites/default/files/documents/Epi-update-BQ1.pdf (2022).</ref>
 
−
<ref name="CNBC XBB.1.5">Highly immune evasive omicron XBB.1.5 variant is quickly becoming dominant in U.S. as it doubles weekly https://www.cnbc.com/2022/12/30/covid-news-omicron-xbbpoint1point5-is-highly-immune-evasive-and-binds-better-to-cells.html (2023).</ref>
 
−
<ref name="XBB.1.5">Yue, C. ''et al''. Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion. Preprint at https://www.biorxiv.org/content/10.1101/2023.01.03.522427v2 (2023).</ref>
 
−
<ref name="Weisblum_eLife">Weisblum, Y. ''et al.'' Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. ''eLife'' '''9,''' (2020).</ref>
 
−
<ref name="CellRep20220517">Westendorf, K. ''et al.'' LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. ''Cell Rep'' '''39,''' 110812 (2022).</ref>
 
−
<ref name="VanBlargan2022">VanBlargan, L. A. ''et al.'' An infectious SARS-CoV-2 B.1.1.529 omicron virus escapes neutralization by therapeutic monoclonal antibodies. ''Nat Med'' '''28,''' 490–495 (2022).</ref>
 
−
<ref name="KempCIP">Kemp, S. A. ''et al''. SARS-CoV-2 evolution during treatment of chronic infection. ''Nature'' '''592''', 277–282 (2021).</ref>
 
 
</references>
 
</references>
  
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[[Category:deLemus]]

Latest revision as of 10:25, 15 December 2023

Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoproteins


The dynamic epidemiology of coronavirus disease 2019 (COVID-19) since its outbreak has been a result of the continuous evolution of its etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), namely alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2), together with numerous variants of interest (VOI). The latest lineage to be designated a VOC would be omicron (B.1.1.529),[1] from which a diverse variant soup is generated.[2] From the original BA.1 strain of November 2021 to the most recent XBB and BQ.1 strains of late 2022,[3][4] each omicron subvariant has successively proliferated and outcompeted its once dominant antecedent.[5] The emergence of all these variants has brought along many novel mutations that continue to fine-tune the fitness of the virus,[6][7] leading to its persistent global circulation. Recent emerging variant (EV) data retrieved from GISAID, as of 17 January 2023, has revealed that the top 4 most rapidly spreading lineages are the BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1 variants, among which XBB.1.5 has been found to be especially prevalent in the US,[8] making up of more than 40% of its sequence coverage in early January 2023.

Spike Glycoprotein

The spike glycoprotein of SARS-CoV-2 is a trimeric type I viral fusion protein that binds the virus to the angiotensin-converting enzyme 2 (ACE2) receptor of a host cell.[9] It is composed of 2 subunits: the N-terminal subunit 1 (S1) and C-terminal subunit 2 (S2), within which multiple domains lie. The S1 region facilitates ACE2 binding and is made up of an N-terminal domain (NTD), a receptor-binding domain (RBD), and 2 C-terminal subdomains (CTD1 and CTD2), while the downstream S2 region is responsible for mediating virus-host cell membrane fusion.

Update

The identified leading mutations in 2023 are listed as follows [10]:

2023.12.01-2023.12.17

Outlined Mutations Confirmed in VOC/Emerging Variants
L455F EG.5.1.1
A475V EG.5.1.1
E654K HK.3

2023.11.01-2023.11.17

Outlined Mutations Confirmed in VOC/Emerging Variants
N185D HK.3.2
L455F EG.5.1.1
A475V JF.1
T572I FY.2
Q613H XBB.1.16
D1153Y HK.3

2023.10.06

Outlined Mutations Confirmed in VOC/Emerging Variants
L455F EG.5.1.1
A475V GK.1

2023.09.08-2023.09.28

Outlined Mutations Confirmed in VOC/Emerging Variants
R403K BA.2.86 (Pirola)
L455F EG.5.1.1
S494P EG.5.1.1
P521S XBB.1.16.15
E554K BA.2.86 (Pirola) & FE.1
Q613H BA.2.86 (Pirola)
P621S BA.2.86 (Pirola)
T732I XBB.2.3 x XBB.1.5
S939F BA.2.86 (Pirola)
V1264L CK.1.1

Here are the recently confirmed leading mutations.

2023.08.04 - 2023.08.22

Outlined Mutations Confirmed in VOC/Emerging Variants
N185D XBB.1.5
L212S FY.4.2
V445A XBC.1.6
L455F EG.5.1.1
F456L EG.5.1 (Eris)
E554Q XBB.1.5.18
Q613H XBB.1.16
T883I XBB.1.16

*The reported mutations of detected variants are from Cov-Lineages[11]

RBD Mutation Profile of Latest VOIs.

  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.06.30 - 2023.07.05

Outlined Mutations Confirmed in VOC/Emerging Variants
H146K FL.2.3 (XBB.1.9.1.2.3)
S446N FL.19
F456L XBF


  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.06.01 - 2023.06.13

Outlined Mutations Confirmed in VOC/Emerging Variants
F490P XBB.1.9.1
E554K XBB.1.9.1 (sublineage)
Q675K XBB.1.22.1
L858I CH.1.1.1


  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.05.01 - 2023.05.12

Outlined Mutations Confirmed in VOC/Emerging Variants
F456L FD.1.1 & EG.5.1 (2023.08)
S494P XBB.2.3 & XBB.1.1
T572I FY.1 ( XBB.1.22.1.1 )

*The reported mutations of detected variants are from GISAID


  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.04.01 - 2023.04.21

Outlined Mutations Confirmed in VOC/Emerging Variants
H146K XBB.1.5 & XBB.1.16
M153I XBB.2.3.3
E180V XBB.1.16
K444R XBB.1.5
T478R XBB.1.16, XBB.1.5, CH.1.1.2 & XBB.2.3
F490P XBB.2.6
S494P XBB.1.5
Q613H XBB.1.16
P621S XBB.2.3
A688V XAY.1.1.1

  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.03.01 - 2023.03.21

Outlined Mutations Confirmed in VOC/Emerging Variants
Y248S BQ.1
F490P XBB.1 & XBB.1.5
T547I XBB.1.16
Q613H DV.1, CH.1.1.1 & CH.1.1.17
I666V XBB.1.5
V1264L CH.1.1

  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.02.03 - 2023.02.20

Outlined Mutations Confirmed in VOC/Emerging Variants
K147I XBB.1.5.2.1
Y248S BQ.1.1.43
S494P XBB.1.5
Q613H XBB.1.9.2 & XBB.2.4
P612S XBF
T678I BA.2.75 x BA.5
N679R CH.1.1
P1162S XBK.1

*The reported mutations of detected variants are from GISAID[12]

  • Generated 3D structure of spike protein with highlighted leading mutations (AlphaFold2, colab version 2022).

Here are the recently confirmed leading mutations.

2023.01.31

Outlined Mutations Confirmed in VOC/Emerging Variants
V445A BQ.1.1
T883I BQ.1.1

2023.01.17 - 2023.01.25

Outlined Mutations Confirmed in VOC/Emerging Variants
H146- / H146K BQ.1.1 / XBB.1.5
F486A BQ.1.1
E583D BQ.1.1
Q613H BQ.1.1
S939F BQ.1.1


References

  1. ↑ Karim, S. S. A. & Karim, Q. A. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 398, 2126 (2021).
  2. ↑ Callaway, E. COVID ‘variant soup’ is making winter surges hard to predict. Nature 611, 213 (2022).
  3. ↑ Wang, Q. et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 186, 279 (2023).
  4. ↑ Qu, P. et al. Enhanced Neutralization Resistance of SARS-CoV-2 Omicron Subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. Cell Host Microbe 31, 9 (2023)
  5. ↑ Rössler, A. et al. BA.2 and BA.5 Omicron Differ Immunologically from Both BA.1 Omicron and Pre-Omicron Variants. Nat Commun 13, 7701 (2022)
  6. ↑ Carabelli, A. M. et al. SARS-CoV-2 variant biology: Immune escape, transmission and fitness. Nat Rev Microbiol (2023). DOI: https://doi.org/10.1038/s41579-022-00841-7.
  7. ↑ Witte, L. et al. Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape. Nat Commun 14, 302 (2023).
  8. ↑ Callaway, E. Coronavirus variant XBB.1.5 rises in the United States — is it a global threat? Nature 613, 222 (2023).
  9. ↑ Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 23, 3 (2021).
  10. ↑ deLemus team, Analysis of Leading Mutations in SARS-CoV-2 Spike Glycoproteins (in preparation, 2023).
  11. ↑ Cov-Lineages https://cov-lineages.org/
  12. ↑ GISAID https://gisaid.org/


Map

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