Genome-wide CRISPR activation screen identifies candidate receptors for SARS-CoV-2 entry

Zhu, Shifan; Liu, Ying; Zhou, Zhuo; Zhang, Zhiying; Xiao, Xia; Liu, Zhiheng; Chen, Ang; Dong, Xuan; Tian, Feng; Chen, Shihua; Xu, Yiyuan; Wang, Chunhui; Li, Qiheng; Niu, Xuran; Qian, Ping; Du, Shuo; Xiao, Junyu; Wang, Jianwei; Wei, Wensheng

doi:10.1007/s11427-021-1990-5

Cited by 52 publications

(53 citation statements)

References 55 publications

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“…Instead, we suppose that NTD mutations might modulate some functional properties of this domain, which unfortunately remains experimentally understudied. The described NTD functions include controlling S-protein conformation ( Li et al., 2021 ), interaction with host surface sialosides ( Awasthi et al., 2020 ) and, most recently, binding to alternative entry receptors ( Zhu et al., 2021 ). The second hot spot – the RBD domain shows a strong accumulation of mutations at the binding interface with the ACE2 receptor (see below for a dedicated paragraph).…”

Section: Resultsmentioning

confidence: 99%

Perspectives: SARS-CoV-2 Spike Convergent Evolution as a Guide to Explore Adaptive Advantage

Zahradník

Nunvář

Schreiber

2022

Front. Cell. Infect. Microbiol.

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Viruses rapidly co-evolve with their hosts. The 9 million sequenced SARS-CoV-2 genomes by March 2022 provide a detailed account of viral evolution, showing that all amino acids have been mutated many times. However, only a few became prominent in the viral population. Here, we investigated the emergence of the same mutations in unrelated parallel lineages and the extent of such convergent evolution on the molecular level in the spike (S) protein. We found that during the first phase of the pandemic (until mid 2021, before mass vaccination) 31 mutations evolved independently ≥3-times within separated lineages. These included all the key mutations in SARS-CoV-2 variants of concern (VOC) at that time, indicating their fundamental adaptive advantage. The omicron added many more mutations not frequently seen before, which can be attributed to the synergistic nature of these mutations, which is more difficult to evolve. The great majority (24/31) of S-protein mutations under convergent evolution tightly cluster in three functional domains; N-terminal domain, receptor-binding domain, and Furin cleavage site. Furthermore, among the S-protein receptor-binding motif mutations, ACE2 affinity-improving substitutions are favoured. Next, we determined the mutation space in the S protein that has been covered by SARS-CoV-2. We found that all amino acids that are reachable by single nucleotide changes have been probed multiple times in early 2021. The substitutions requiring two nucleotide changes have recently (late 2021) gained momentum and their numbers are increasing rapidly. These provide a large mutation landscape for SARS-CoV-2 future evolution, on which research should focus now.

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Section: Resultsmentioning

confidence: 99%

Perspectives: SARS-CoV-2 Spike Convergent Evolution as a Guide to Explore Adaptive Advantage

Zahradník

Nunvář

Schreiber

2022

Front. Cell. Infect. Microbiol.

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“…This has included acquisition of the ability for heparin sulfate mediated infection of an ACE2-negative human lung epithelial as a result of the E484D mutation in the RBD(29), indeed in vitro evolution of SARS-CoV-2 to higher infectivity through more efficient binding to heparin sulfate has been reported(30), and in vivo reduction of intestinal ACE2 expression did not impact SARS-CoV-2 infection or severity(31), further suggesting the contribution of other cellular entry mechanisms. Several other receptors have been reported to facilitate ACE2-independent SARS-CoV-2 infection, including the tyrosine-protein kinase receptor UFO (AXL)(32), LDLRAD3, and CLEC4G(33). While it is almost certain that the current SARS-CoV-2 VoC ravaging humanity are highly dependent on ACE2, as the high level of viral burden among the world’s population continues, increasingly in people with pre-existing Abs to SARS-CoV-2 through prior infection or vaccination, S2 hmAbs may provide protection against possible future variations in attachment receptor utilization by CoV.…”

Section: Discussionmentioning

confidence: 99%

Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody

Piepenbrink

Park

Deshpande

et al. 2022

Preprint

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development.

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“…Studies have confirmed that, in addition to ACE2 and CD147, SARS-CoV-2 can enter host cells by binding to some other receptors. Recent research hotspots include Cathepsin L1 ( Aguiar et al, 2020 ), integrins αvβ3 and αvβ6 ( Calver et al, 2021 ), and even low-density lipoprotein receptor class A domain containing 3 (LDLRAD3) and C- type lectin domain family 4 member G (CLEC4G) ( Zhu et al, 2021 ). The pathologic consequences of SARS-COV-2 binding to these receptors are uncertain.…”

Section: Introductionmentioning

confidence: 99%

The Interaction Between Pulmonary Fibrosis and COVID-19 and the Application of Related Anti-Fibrotic Drugs

et al. 2022

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COVID-19 is a highly contagious respiratory disease, which mainly affects the lungs. Critically ill patients are easily complicated by cytokine storms, acute respiratory distress syndrome (ARDS), and respiratory failure, which seriously threaten their lives. Pulmonary fibrosis (PF) is a common interstitial lung disease, and its pathogenesis may involve the participation of a variety of immune cells and inflammatory factors. Current studies have shown that patients with COVID-19 may be complicated by pulmonary fibrosis, and patients with pulmonary fibrosis may also be at higher risk of contracting COVID-19 than healthy people. Pulmonary fibrosis is an important risk factor leading to the aggravation of COVID-19 disease. COVID-19 complicated by cytokine storm and ARDS mechanism pathways are similar to the pathogenesis of pulmonary fibrosis. The potential interaction between pulmonary fibrosis and COVID-19 can cause acute exacerbation of the patient’s condition, but the potential mechanism between the two has not been fully elucidated. Most of the drug treatment programs for COVID-19-related pulmonary fibrosis are currently formulated about the relevant guidelines for idiopathic pulmonary fibrosis (IPF), and there is no clear drug treatment program recommendation. This article aims to summarize the relevant mechanism pathways of COVID-19 and pulmonary fibrosis, explore the interrelationships and possible mechanisms, and discuss the value and risks of existing and potential COVID-19-related pulmonary fibrosis treatment drugs, to provide reference for anti-fibrosis treatment for patients.

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Genome-wide CRISPR activation screen identifies candidate receptors for SARS-CoV-2 entry

Cited by 52 publications

References 55 publications

Perspectives: SARS-CoV-2 Spike Convergent Evolution as a Guide to Explore Adaptive Advantage

Perspectives: SARS-CoV-2 Spike Convergent Evolution as a Guide to Explore Adaptive Advantage

Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody

The Interaction Between Pulmonary Fibrosis and COVID-19 and the Application of Related Anti-Fibrotic Drugs

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