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Causes and Consequences of Coronavirus Spike Protein Variability

Zech et al., Viruses, doi:10.3390/v16020177

Jan 2024

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Review of causes and consequences of coronavirus spike protein variability focused on SARS-CoV-2. Authors discuss initial features of the SARS-CoV-2 spike protein and subsequent adaptations to the human host that may have enabled the COVID-19 pandemic. The polybasic furin cleavage site insertion is noted as potentially playing a key role in rapid spread. Later changes are highlighted as mainly promoting immune evasion, though some also increased infectivity. Ongoing evolution of variants like XBB is outlined, with mutations in the receptor binding domain evading neutralizing antibodies. Approaches for broad-spectrum vaccines or therapeutics are considered, including conserved epitope targeting and fusion inhibitors, though challenges remain for durable protection against emerging variants.

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Zech et al., 25 Jan 2024, peer-reviewed, 4 authors. Contact: fabian.zech@uni-ulm.de (corresponding author), christoph.jung@kit.edu, timo.jacob@uni-ulm.de, frank.kirchhoff@uni-ulm.de.

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Causes and Consequences of Coronavirus Spike Protein Variability

Fabian Zech, Christoph Jung, Timo Jacob, Frank Kirchhoff

Viruses, doi:10.3390/v16020177

Coronaviruses are a large family of enveloped RNA viruses found in numerous animal species. They are well known for their ability to cross species barriers and have been transmitted from bats or intermediate hosts to humans on several occasions. Four of the seven human coronaviruses (hCoVs) are responsible for approximately 20% of common colds (hCoV-229E, -NL63, -OC43, -HKU1). Two others (SARS-CoV-1 and MERS-CoV) cause severe and frequently lethal respiratory syndromes but have only spread to very limited extents in the human population. In contrast the most recent human hCoV, SARS-CoV-2, while exhibiting intermediate pathogenicity, has a profound impact on public health due to its enormous spread. In this review, we discuss which initial features of the SARS-CoV-2 Spike protein and subsequent adaptations to the new human host may have helped this pathogen to cause the COVID-19 pandemic. Our focus is on host forces driving changes in the Spike protein and their consequences for virus infectivity, pathogenicity, immune evasion and resistance to preventive or therapeutic agents. In addition, we briefly address the significance and perspectives of broad-spectrum therapeutics and vaccines.

Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/v16020177/s1, Table S1 : GenBank identifiers of analysed Spike proteins (Figure 1 /2). Author Contributions: F.Z. and F.K. wrote the manuscript. F.Z. and C.J. drafted the figures and F.K. modified and revised them. T.J. provided resources and supervised structural analyses. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors have no conflicts of interest to declare.

References

Addetia, Park, Starr, Greaney, Sprouse et al., Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail, Cell Rep, doi:10.1016/j.celrep.2023.112621

Adhikary, Kandel, Mamani, Mustafa, Hao et al., Discovery of Small Anti-ACE2 Peptides to Inhibit SARS-CoV-2 Infectivity, Adv. Ther, doi:10.1002/adtp.202100087

Andersen, Rambaut, Lipkin, Holmes, Garry, The proximal origin of SARS-CoV-2, Nat. Med, doi:10.1038/s41591-020-0820-9

Ao, He, Hong, Wei, The rapid rise of SARS-CoV-2 Omicron subvariants with immune evasion properties: XBB.1.5 and BQ.1.1 subvariants, MedComm, doi:10.1002/mco2.239

Arieta, Xie, Rothenberg, Diao, Harjanto et al., The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection, Cell, doi:10.1016/j.cell.2023.04.007

Baggen, Jacquemyn, Persoons, Vanstreels, Pye et al., TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry, Cell, doi:10.1016/j.cell.2023.06.005

Banerjee, Kulcsar, Misra, Frieman, Mossman et al., None, Viruses, doi:10.3390/v11010041

Basile, Zannella, De Marco, Sanna, Franci et al., Spike-mediated viral membrane fusion is inhibited by a specific anti-IFITM2 monoclonal antibody, Antivir. Res, doi:10.1016/j.antiviral.2023.105546

Belik, Liedes, Vara, Haveri, Pöysti et al., Persistent T cell-mediated immune responses against Omicron variants after the third COVID-19 mRNA vaccine dose, Front. Immunol, doi:10.3389/fimmu.2023.1099246

Benton, Wrobel, Xu, Roustan, Martin et al., Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion, Nature, doi:10.1038/s41586-020-2772-0

Bermingham, Chand, Brown, Aarons, Tong et al., Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012, Eurosurveillance, doi:10.2807/ese.17.40.20290-en

Bestle, Heindl, Limburg, Van, Pilgram et al., TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells, Life Sci. Alliance, doi:10.26508/lsa.202000786

Bhattacharya, Chatterjee, Sharma, Agoramoorthy, Chakraborty, D614G mutation and SARS-CoV-2: Impact on S-protein structure, function, infectivity, and immunity, Appl. Microbiol. Biotechnol, doi:10.1007/s00253-021-11676-2

Biancolella, Colona, Mehrian-Shai, Watt, Luzzatto et al., Transition of the pandemic to the endemic phase, Hum. Genom, doi:10.1186/s40246-022-00392-1

Boni, Lemey, Jiang, Lam, Perry et al., Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic, Nat. Microbiol, doi:10.1038/s41564-020-0771-4

Cantoni, Mayora-Neto, Thakur, Elrefaey, Newman et al., Pseudotyped Bat Coronavirus RaTG13 is efficiently neutralised by convalescent sera from SARS-CoV-2 infected patients, Commun. Biol, doi:10.1038/s42003-022-03325-9

Cao, Cai, Xiao, Rao, Chen et al., The architecture of the SARS-CoV-2 RNA genome inside virion, Nat. Commun, doi:10.1038/s41467-021-22785-x

Cao, Goreshnik, Coventry, Case, Miller et al., De novo design of picomolar SARS-CoV-2 miniprotein inhibitors, Science, doi:10.1126/science.abd9909

Cao, Jian, Wang, Yu, Song et al., Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution, Nature, doi:10.1038/s41586-022-05644-7

Cao, Wang, Jian, Xiao, Song et al., Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies, Nature, doi:10.1038/s41586-021-04385-3

Carabelli, Peacock, Thorne, Harvey, Hughes, COVID-19

Chakraborty, Sharma, Bhattacharya, Lee, A Detailed Overview of Immune Escape, Antibody Escape, Partial Vaccine Escape of SARS-CoV-2 and Their Emerging Variants With Escape Mutations, Front. Immunol, doi:10.3389/fimmu.2022.801522

Chan, Chu, Wang, Wong, Zhao et al., Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 Is an Important Surface Attachment Factor That Facilitates Entry of Middle East Respiratory Syndrome Coronavirus, J. Virol, doi:10.1128/JVI.01133-16

Chan, Zhan, The Emergence of the Spike Furin Cleavage Site in SARS-CoV-2, Mol. Biol. Evol, doi:10.1093/molbev/msab327

Chen, Zhao, Zhou, Zhu, Jiang et al., Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses, Nat. Rev. Immunol, doi:10.1038/s41577-022-00784-3

Cheng, Chao, Li, Chiu, Kao et al., Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects, Cell Rep, doi:10.1016/j.celrep.2020.108254

Choe, Farzan, How SARS-CoV-2 first adapted in humans: An early spike protein mutation promotes transmission and will shape the next vaccines, Science, doi:10.1126/science.abi4711

Cohen, Spiro, Viboud, Projecting the SARS-CoV-2 transition from pandemicity to endemicity: Epidemiological and immunological considerations, PLoS Pathog, doi:10.1371/journal.ppat.1010591

Corman, Muth, Niemeyer, Drosten, Hosts and Sources of Endemic Human Coronaviruses, Adv. Virus Res, doi:10.1016/bs.aivir.2018.01.001

Cosar, Karagulleoglu, Unal, Ince, Uncuoglu et al., SARS-CoV-2 Mutations and their Viral Variants, Cytokine Growth Factor Rev, doi:10.1016/j.cytogfr.2021.06.001

Coutard, Valle, De Lamballerie, Canard, Seidah et al., The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade, Antivir. Res, doi:10.1016/j.antiviral.2020.104742

Cui, Li, Shi, Origin and evolution of pathogenic coronaviruses, Nat. Rev. Microbiol, doi:10.1038/s41579-018-0118-9

Dangi, Palacio, Sanchez, Park, Class et al., Cross-protective immunity following coronavirus vaccination and coronavirus infection, J. Clin. Investig, doi:10.1172/JCI151969

Daniloski, Jordan, Ilmain, Guo, Bhabha et al., The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types, eLife, doi:10.7554/eLife.65365

De Maio, Walker, Turakhia, Lanfear, Corbett-Detig et al., Mutation Rates and Selection on Synonymous Mutations in SARS-CoV-2, Genome Biol. Evol, doi:10.1093/gbe/evab087

Dhama, Patel, Sharun, Pathak, Tiwari et al., SARS-CoV-2 jumping the species barrier: Zoonotic lessons from SARS, MERS and recent advances to combat this pandemic virus, Travel Med. Infect. Dis, doi:10.1016/j.tmaid.2020.101830

Eckerle, Becker, Halpin, Li, Venter et al., Infidelity of SARS-CoV Nsp14-Exonuclease Mutant Virus Replication Is Revealed by Complete Genome Sequencing, PLoS Pathog, doi:10.1371/journal.ppat.1000896

Evans, Tan, Aung, Phyu, Lin et al., Exposure to diverse sarbecoviruses indicates frequent zoonotic spillover in human communities interacting with wildlife, Int. J. Infect. Dis, doi:10.1016/j.ijid.2023.02.015

Feng, Yuan, Powers, Hu, Munt et al., Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine, Sci. Transl. Med, doi:10.1126/scitranslmed.adg7404

Focosi, Maggi, Recombination in Coronaviruses, with a Focus on SARS-CoV-2, Viruses, doi:10.3390/v14061239

Folegatti, Ewer, Aley, Angus, Becker et al., Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1/2, single-blind, randomised controlled trial, Lancet, doi:10.1016/S0140-6736(20)31604-4

Hachmann, Miller, Collier, Ventura, Yu et al., Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA

Halfmann, Iida, Iwatsuki-Horimoto, Maemura, Kiso et al., SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters, Nature, doi:10.1038/s41586-022-04441-6

Hao, Cheng, Wu, Wu, Lin et al., Reconstruction of the full transmission dynamics of COVID-19 in Wuhan, Nature, doi:10.1038/s41586-020-2554-8

Hoffmann, Arora, Nehlmeier, Kempf, Cossmann et al., Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5, Cell. Mol. Immunol, doi:10.1038/s41423-023-00988-0

Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, doi:10.1016/j.cell.2020.02.052

Hofmann, Pyrc, Van Der Hoek, Geier, Berkhout et al., Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry, Proc. Natl. Acad. Sci, doi:10.1073/pnas.0409465102

Hu, Chan, Liu, Liu, Chai et al., Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2, Emerg. Microbes Infect, doi:10.1080/22221751.2022.2117098

Ito, Suzuki, Uriu, Itakura, Zahradnik et al., Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant, Nat. Commun, doi:10.1038/s41467-023-38188-z

Jackson, Farzan, Chen, Choe, Mechanisms of SARS-CoV-2 entry into cells, Nat. Rev. Mol. Cell Biol, doi:10.1038/s41580-021-00418-x

Jones, Mourão, Czarna, Matsuda, Fino et al., Characterization of SARS-CoV-2 replication complex elongation and proofreading activity, Sci. Rep, doi:10.1038/s41598-022-13380-1

Jung, Kmiec, Koepke, Zech, Jacob et al., Omicron: What makes the latest SARS-CoV-2 variant of concern so concerning?, J. Virol, doi:10.1128/jvi.02077-21

Karoyan, Vieillard, Gómez-Morales, Odile, Guihot et al., Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection, Commun. Biol, doi:10.1038/s42003-021-01736-8

Keusch, Amuasi, Anderson, Daszak, Eckerle et al., Pandemic origins and a One Health approach to preparedness and prevention: Solutions based on SARS-CoV-2 and other RNA viruses, Proc. Natl. Acad. Sci, doi:10.1073/pnas.2202871119

Korber, Fischer, Gnanakaran, Yoon, Theiler et al., Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus, Cell, doi:10.1016/j.cell.2020.06.043

Ksiazek, Erdman, Goldsmith, Zaki, Peret et al., A novel coronavirus associated with severe acute respiratory syndrome, N. Engl. J. Med, doi:10.1056/NEJMoa030781

Larue, Xing, Kenney, Zhang, Tuazon et al., Rationally Designed ACE2-Derived Peptides Inhibit SARS-CoV-2, Bioconjug. Chem, doi:10.1021/acs.bioconjchem.0c00664

Lawrenz, Xie, Zech, Weil, Seidel et al., Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination Boosts Neutralizing Activity Against Seasonal Human Coronaviruses, Clin. Infect. Dis, doi:10.1093/cid/ciac057

Lee, Zepeda, Park, Taylor, Quispe et al., Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus, Cell Host Microbe, doi:10.1016/j.chom.2023.10.018

Letko, Marzi, Munster, Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses, Nat. Microbiol, doi:10.1038/s41564-020-0688-y

Lim, Zhang, Chang, ACE2-Independent Alternative Receptors for SARS-CoV-2, Viruses, doi:10.3390/v14112535

Liu, Iketani, Guo, Chan, Wang et al., Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2, Nature, doi:10.1038/s41586-021-04388-0

Lopez Bernal, Andrews, Gower, Gallagher, Simmons et al., Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant, N. Engl. J. Med, doi:10.1056/NEJMoa2108891

Lubinski, Fernandes, Frazier, Tang, Daniel et al., Functional evaluation of the P681H mutation on the proteolytic activation of the SARS-CoV-2 variant B.1.1.7 (Alpha) spike, iScience, doi:10.1016/j.isci.2021.103589

Mahdy, Younis, Ewaida, An Overview of SARS-CoV-2 and Animal Infection, Front. Vet. Sci, doi:10.3389/fvets.2020.596391

Markov, Ghafari, Beer, Lythgoe, Simmonds et al., The evolution of SARS-CoV-2, Nat. Rev. Microbiol, doi:10.1038/s41579-023-00878-2

Martin, Weaver, Tegally, San, Shank et al., The emergence and ongoing convergent evolution of the SARS-CoV-2 N501Y lineages, Cell, doi:10.1016/j.cell.2021.09.003

Martinez, Schäfer, Gavitt, Mallory, Lee et al., Vaccine-mediated protection against Merbecovirus and Sarbecovirus challenge in mice, Cell Rep, doi:10.1016/j.celrep.2023.113248

Mccallum, Czudnochowski, Rosen, Zepeda, Bowen et al., Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement, Science, doi:10.1126/science.abn8652

Meng, Abdullahi, Ferreira, Goonawardane, Saito et al., Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity, Nature, doi:10.1038/s41586-022-04474-x

Moeller, Shi, Demir, Belica, Banerjee et al., Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN, Proc. Natl. Acad. Sci, doi:10.1073/pnas.2106379119

Müller, Maus, Hammerschmidt, Knaff, Mailänder et al., Interfering with Host Proteases in SARS-CoV-2 Entry as a Promising Therapeutic Strategy, Curr. Med. Chem, doi:10.2174/0929867328666210526111318

Nassar, Ibrahim, Amin, Magdy, Elgharib et al., A Review of Human Coronaviruses' Receptors: The Host-Cell Targets for the Crown Bearing Viruses, Molecules, doi:10.3390/molecules26216455

Nchioua, Diofano, Noettger, Von Maltitz, Stenger et al., Strong attenuation of SARS-CoV-2 Omicron BA.1 and increased replication of the BA.5 subvariant in human cardiomyocytes, Signal Transduct. Target. Ther, doi:10.1038/s41392-022-01256-9

Nchioua, Schundner, Kmiec, Prelli Bozzo, Zech et al., SARS-CoV-2 Variants of Concern Hijack IFITM2 for Efficient Replication in Human Lung Cells, J. Virol, doi:10.1128/jvi.00594-22

Ou, Liu, Lei, Li, Mi et al., Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV, Nat. Commun, doi:10.1038/s41467-020-15562-9

Owczarek, Szczepanski, Milewska, Baster, Rajfur et al., Early events during human coronavirus OC43 entry to the cell, Sci. Rep, doi:10.1038/s41598-018-25640-0

Park, Pinto, Walls, Liu, De Marco et al., Imprinted antibody responses against SARS-CoV-2 Omicron sublineages, Science, doi:10.1126/science.adc9127

Pastorio, Noettger, Nchioua, Zech, Sparrer et al., Impact of mutations defining SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 on Spike function and neutralization, iScience, doi:10.1016/j.isci.2023.108299

Pastorio, Zech, Noettger, Jung, Jacob et al., Determinants of Spike infectivity, processing, and neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2, Cell Host Microbe, doi:10.1016/j.chom.2022.07.006

Peacock, Barclay, De Silva, Towers, SARS-CoV-2 variant biology: Immune escape, transmission and fitness, Nat. Rev. Microbiol, doi:10.1038/s41579-022-00841-7

Peacock, Goldhill, Zhou, Baillon, Frise et al., The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets, Nat. Microbiol, doi:10.1038/s41564-021-00908-w

Piccoli, Park, Tortorici, Czudnochowski, Walls et al., Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology, Cell, doi:10.1016/j.cell.2020.09.037

Pinto, Sauer, Czudnochowski, Low, Tortorici et al., Broad betacoronavirus neutralization by a stem helix-specific human antibody, Science, doi:10.1126/science.abj3321

Planas, Saunders, Maes, Guivel-Benhassine, Planchais et al., Considerable escape of SARS-CoV-2 variant Omicron to antibody neutralization, Nature, doi:10.1038/s41586-021-04389-z

Plante, Liu, Liu, Xia, Johnson et al., Spike mutation D614G alters SARS-CoV-2 fitness, Nature, doi:10.1038/s41586-020-2895-3

Polack, Thomas, Kitchin, Absalon, Gurtman et al., Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine, N. Engl. J. Med, doi:10.1056/NEJMoa2034577

Posani, Dilucca, Forcelloni, Pavlopoulou, Georgakilas et al., Temporal evolution and adaptation of SARS-CoV-2 codon usage, Front. Biosci, doi:10.31083/j.fbl2701013

Prelli Bozzo, Nchioua, Volcic, Koepke, Krüger et al., IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro, Nat. Commun, doi:10.1038/s41467-021-24817-y

Qing, Gallagher, Adaptive variations in SARS-CoV-2 spike proteins: Effects on distinct virus-cell entry stages, mBio, doi:10.1128/mbio.00171-23

Qu, Evans, Kurhade, Zeng, Zheng et al., Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants, mBio, doi:10.1128/mbio.03176-22

Sanjuán, Nebot, Chirico, Mansky, Belshaw, Viral Mutation Rates, J. Virol, doi:10.1128/JVI.00694-10

Sasaki, Toba, Itakura, Chambaro, Kishimoto et al., SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity, mBio, doi:10.1128/mBio.01415-21

Saunders, Fernandez, Planchais, Michel, Rajah et al., TMPRSS2 is a functional receptor for human coronavirus HKU1, Nature, doi:10.1038/s41586-023-06761-7

Saunders, Lee, Parks, Martinez, Li et al., Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses, Nature, doi:10.1038/s41586-021-03594-0

Schaefer, Jung, Hummer, Binding of SARS-CoV-2 Fusion Peptide to Host Endosome and Plasma Membrane, J. Phys. Chem. B, doi:10.1021/acs.jpcb.1c04176

Schütz, Ruiz-Blanco, Münch, Kirchhoff, Sanchez-Garcia et al., Peptide and peptide-based inhibitors of SARS-CoV-2 entry, Adv. Drug Deliv. Rev, doi:10.1016/j.addr.2020.11.007

Shi, Simpson, Chen, Aull, Benjamin et al., Mutations accumulated in the Spike of SARS-CoV-2 Omicron allow for more efficient counteraction of the restriction factor BST2/Tetherin, PLoS Pathog, doi:10.1371/journal.ppat.1011912

Shuai, Chan, Hu, Chai, Yoon et al., The viral fitness and intrinsic pathogenicity of dominant SARS-CoV-2 Omicron sublineages BA, eBioMedicine, doi:10.1016/j.ebiom.2023.104753

Stewart, Palmulli, Johansen, Mcgovern, Shehata et al., Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release, EMBO Rep, doi:10.15252/embr.202357224

Stout, Millet, Stanhope, Whittaker, Furin cleavage sites in the spike proteins of bat and rodent coronaviruses: Implications for virus evolution and zoonotic transfer from rodent species, One Health, doi:10.1016/j.onehlt.2021.100282

Tang, Liu, Chen, Human coronaviruses: Origin, host and receptor, J. Clin. Virol, doi:10.1016/j.jcv.2022.105246

Tao, Tzou, Nouhin, Gupta, De Oliveira et al., The biological and clinical significance of emerging SARS-CoV-2 variants, Nat. Rev. Genet, doi:10.1038/s41576-021-00408-x

Telenti, Hodcroft, Robertson, The Evolution and Biology of SARS-CoV-2 Variants, Cold Spring Harb. Perspect. Med, doi:10.1101/cshperspect.a041390

Temmam, Vongphayloth, Baquero, Munier, Bonomi et al., Bat coronaviruses related to SARS-CoV-2 and infectious for human cells, Nature, doi:10.1038/s41586-022-04532-4

Tian, Tong, Sun, Shi, Zheng et al., N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2, eLife, doi:10.7554/eLife.69091

Tosta, The adaptation of SARS-CoV-2 to humans, Mem. Do Inst. Oswaldo Cruz, doi:10.1590/0074-02760210127

Tseng, Ackerson, Sy, Tubert, Luo et al., mRNA-1273 bivalent (original and Omicron) COVID-19 vaccine effectiveness against COVID-19 outcomes in the United States, Nat. Commun, doi:10.1038/s41467-023-41537-7

Van Doremalen, Singh, Saturday, Yinda, Perez-Perez et al., SARS-CoV-2 Omicron BA.1 and BA.2 are attenuated in rhesus macaques as compared to Delta, Sci. Adv, doi:10.1126/sciadv.ade1860

Voysey, Costa Clemens, Madhi, Weckx, Folegatti et al., Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: A pooled analysis of four randomised trials, Lancet, doi:10.1016/S0140-6736(21)00432-3

Vu, Alvarado, Morris, Lokugamage, Zhou et al., Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection, bioRxiv, doi:10.1101/2023.04.17.536926

Walls, Park, Tortorici, Wall, Mcguire et al., Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein, Cell, doi:10.1016/j.cell.2020.02.058

Wang, Guo, Iketani, Nair, Li et al., Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12, BA.4 and BA.5, doi:10.1038/s41586-022-05053-w

Wang, Iketani, Li, Liu, Guo et al., Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants, Cell, doi:10.1016/j.cell.2022.12.018

Wang, Nair, Liu, Iketani, Luo et al., Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7, Nature, doi:10.1038/s41586-021-03398-2

Wang, Noettger, Xie, Pastorio, Seidel et al., Determinants of species-specific utilization of ACE2 by human and animal coronaviruses, Commun. Biol, doi:10.1038/s42003-023-05436-3

Wang, Shi, Jiang, Zhang, Wang et al., Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4, Cell Res, doi:10.1038/cr.2013.92

Weissman, Alameh, De Silva, Collini, Hornsby et al., D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization, Cell Host Microbe, doi:10.1016/j.chom.2020.11.012

Wettstein, Immenschuh, Weil, Conzelmann, Almeida-Hernández et al., Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection, J. Med. Virol, doi:10.1002/jmv.28124

Whittaker, SARS-CoV-2 spike and its adaptable furin cleavage site, Lancet Microbe, doi:10.1016/S2666-5247(21)00174-9

Worobey, Levy, Malpica Serrano, Crits-Christoph, Pekar et al., The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic, Science, doi:10.1126/science.abp8715

Wright, Lakdawala, Cooper, SARS-CoV-2 genome evolution exposes early human adaptations, bioRxiv, doi:10.1101/2020.05.26.117069

Xia, Lan, Zhu, Wang, Xu et al., Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation, Signal Transduct. Target. Ther, doi:10.1038/s41392-021-00712-2

Xia, Wang, Jiao, Yu, Xu et al., SARS-CoV-2 Omicron subvariants exhibit distinct fusogenicity, but similar sensitivity, to pan-CoV fusion inhibitors, Emerg. Microbes Infect, doi:10.1080/22221751.2023.2178241

Xia, Zhang, Wang, Wang, Yang et al., Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: A randomised, double-blind, placebo-controlled, phase 1/2 trial, Lancet Infect. Dis, doi:10.1016/S1473-3099(20)30831-8

Xie, Bozzo, Eiben, Noettger, Kmiec et al., Endogenous IFITMs boost SARS-coronavirus 1 and 2 replication whereas overexpression inhibits infection by relocalizing ACE2, iScience, doi:10.1016/j.isci.2023.106395

Xiong, Cao, Ma, Tortorici, Liu et al., Close relatives of MERS-CoV in bats use ACE2 as their functional receptors, Nature, doi:10.1038/s41586-022-05513-3

Yang, Yu, Xu, Jian, Song et al., Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure, Lancet Infect. Dis, doi:10.1016/S1473-3099(23)00744-2

Ye, Yuan, Yuen, Fung, Chan et al., Zoonotic origins of human coronaviruses, Int. J. Biol. Sci, doi:10.7150/ijbs.45472

Yeager, Ashmun, Williams, Cardellichio, Shapiro et al., Human aminopeptidase N is a receptor for human coronavirus 229E, Nature, doi:10.1038/357420a0

Yu, Zheng, Zhou, Li, Chen et al., SARS-CoV-2 spike engagement of ACE2 primes S2 ′ site cleavage and fusion initiation, Proc. Natl. Acad. Sci, doi:10.1073/pnas.2111199119

Yu, Zhu, Yan, Wu, Chong et al., Pan-coronavirus fusion inhibitors possess potent inhibitory activity against HIV-1, HIV-2, and simian immunodeficiency virus, Emerg. Microbes Infect, doi:10.1080/22221751.2021.1917309

Yue, Song, Wang, Jian, Chen et al., ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5, Lancet Infect. Dis, doi:10.1016/S1473-3099(23)00010-5

Yurkovetskiy, Wang, Pascal, Tomkins-Tinch, Nyalile et al., Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant, Cell, doi:10.1016/j.cell.2020.09.032

Zech, Schniertshauer, Jung, Herrmann, Cordsmeier et al., Spike residue 403 affects binding of coronavirus spikes to human ACE2, Nat. Commun, doi:10.1038/s41467-021-27180-0

Zhang, Jackson, Mou, Ojha, Peng et al., SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity, Nat. Commun, doi:10.1038/s41467-020-19808-4

Zhang, Wu, Zhang, Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak, Curr. Biol, doi:10.1016/j.cub.2020.03.022

Zhang, Xiang, Huo, Zhou, Jiang et al., Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy, Signal Transduct. Target. Ther, doi:10.1038/s41392-021-00653-w

Zhao, Yang, Yang, Zhang, Huang et al., Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development, Signal Transduct. Target. Ther, doi:10.1038/s41392-021-00558-8

Zheng, Zhao, Zheng, Chen, Du et al., Bat SARS-Like WIV1 coronavirus uses the ACE2 of multiple animal species as receptor and evades IFITM3 restriction via TMPRSS2 activation of membrane fusion, Emerg. Microbes Infect, doi:10.1080/22221751.2020.1787797

Zhou, Song, Liu, Yuan, He et al., Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease, Immunity, doi:10.1016/j.immuni.2023.02.005

Zhou, Yang, Wang, Hu, Zhang et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature, doi:10.1038/s41586-020-2012-7

Zmasek, Lefkowitz, Niewiadomska, Scheuermann, Genomic evolution of the Coronaviridae family, Virology, doi:10.1016/j.virol.2022.03.005

Örd, Faustova, Loog, The sequence at Spike S1/S2 site enables cleavage by furin and phospho-regulation in SARS-CoV2 but not in SARS-CoV1 or MERS-CoV, Sci. Rep, doi:10.1038/s41598-020-74101-0

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

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