Intrinsic D614G and P681R/H mutations in SARS-CoV-2 VoCs Alpha, Delta, Omicron and viruses with D614G plus key signature mutations in spike protein alters fusogenicity and infectivity DOI Creative Commons
Ritika Khatri,

Gazala Siddqui,

Srikanth Sadhu

et al.

Medical Microbiology and Immunology, Journal Year: 2022, Volume and Issue: 212(1), P. 103 - 122

Published: Dec. 30, 2022

Abstract The SARS-CoV-2 virus has been rapidly evolving over the time and genetic variation led to generation of Variants Concerns (VoC), which have shown increased fitness. These VoC viruses contain key mutations in spike protein allowed better survival evasion host defense mechanisms. D614G mutation domain is found majority VoC; additionally, P681R/H at S1/S2 furin cleavage site junction also be highly conserved major VoCs; Alpha, Delta, Omicron, its’ current variants. impact these alterations VoCs on cell entry, transmissibility, infectivity not clearly identified. In our study, Delta + P681R synthetic double mutant pseudoviruses showed a significant increase cell-to-cell fusion infectivity. contrast, Omicron P681H single TMPRSS2 independent less as compared mutants. Addition exogenous trypsin further enhanced Omicron. Furthermore, susceptibility both E64d Camostat mesylate inhibitors suggesting, that could exploit endosomal dependent entry pathways virus. Taken together, results indicate are pivotal might favoring replication different compartments, thus allowing balance vs selection for long-term adaptation.

Language: Английский

Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron DOI Open Access
Huiping Shuai, Jasper Fuk‐Woo Chan, Bingjie Hu

et al.

Nature, Journal Year: 2022, Volume and Issue: 603(7902), P. 693 - 699

Published: Jan. 21, 2022

Language: Английский

Citations

618
Therapeutic strategies for COVID-19: progress and lessons learned DOI Open Access
Guangdi Li, Rolf Hilgenfeld, Richard J. Whitley

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

Citations

411
Cellular host factors for SARS-CoV-2 infection DOI Creative Commons
Jim Baggen, Els Vanstreels, Sander Jansen

et al.

Nature Microbiology, Journal Year: 2021, Volume and Issue: 6(10), P. 1219 - 1232

Published: Sept. 1, 2021

The coronavirus disease 2019 (COVID-19) pandemic has claimed millions of lives and caused a global economic crisis. No effective antiviral drugs are currently available to treat infections severe acute respiratory syndrome 2 (SARS-CoV-2). medical need imposed by the spurred unprecedented research efforts study biology. Every virus depends on cellular host factors pathways for successful replication. These proviral represent attractive targets therapy as they genetically more stable than viral may be shared among related viruses. application various 'omics' technologies led rapid discovery that required completion SARS-CoV-2 life cycle. In this Review, we summarize insights into infection were mainly obtained using functional genetic interactome screens. We discuss processes important cycle, well parallels with non-coronaviruses. Finally, highlight could targeted clinically approved molecules in clinical trials potential therapies COVID-19. Proviral infection, replication COVID-19 reviewed.

Language: Английский

Citations

185
Proteolytic activation of SARS‐CoV‐2 spike protein DOI Creative Commons
Makoto Takeda

Microbiology and Immunology, Journal Year: 2021, Volume and Issue: 66(1), P. 15 - 23

Published: Sept. 25, 2021

Spike (S) protein cleavage is a crucial step in coronavirus infection. In this review, process discussed, with particular focus on the novel coronavirus, severe acute respiratory syndrome 2 (SARS-CoV-2). Compared influenza virus and paramyxovirus membrane fusion proteins, activation mechanism of S much more complex. The has two sites (S1/S2 S2'), motif for furin protease at S1/S2 site that results from unique four-amino acid insertion one distinguishing features SARS-CoV-2. viral particle incorporates protein, which already undergone by furin, then undergoes further S2' site, mediated type II transmembrane serine (TMPRSS2), after binding to receptor angiotensin-converting enzyme (ACE2) facilitate plasma membrane. addition, SARS-CoV-2 can enter cell endocytosis be proteolytically activated cathepsin L, although not major mode variants enhanced infectivity have been emerging throughout ongoing pandemic, there close relationship between changes cleavability. All four concern carry D614G mutation, indirectly enhances cleavability furin. P681R mutation delta variant directly increases cleavability, enhancing virulence. Changes significantly impact infectivity, tissue tropism, Understanding these mechanisms critical counteracting pandemic.

Language: Английский

Citations

171
Endothelial cells are not productively infected by SARS‐CoV‐2 DOI Creative Commons
Lilian Schimmel,

Keng Yih Chew,

Claudia J. Stocks

et al.

Clinical & Translational Immunology, Journal Year: 2021, Volume and Issue: 10(10)

Published: Jan. 1, 2021

Thrombotic and microvascular complications are frequently seen in deceased COVID-19 patients. However, whether this is caused by direct viral infection of the endothelium or inflammation-induced endothelial activation remains highly contentious.Here, we use patient autopsy samples, primary human cells an vitro model pulmonary epithelial-endothelial cell barrier.We show that express very low levels SARS-CoV-2 receptor ACE2 protease TMPRSS2, which blocks their capacity for productive infection, limits to produce infectious virus. Accordingly, can only be infected when they overexpress ACE2, exposed high concentrations SARS-CoV-2. We also does not infect 3D vessels under flow conditions. further demonstrate a co-culture with Endothelial do however sense respond adjacent epithelial cells, increasing ICAM-1 expression releasing pro-inflammatory cytokines.Taken together, these data suggest vivo, unlikely may occur if epithelium denuded (basolateral infection) load present blood (apical infection). In such scenario, whilst occur, it contribute amplification. still play key role pathogenesis sensing mounting response

Language: Английский

Citations

125
A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells DOI Open Access
Drake M. Mellott, Chien‐Te K. Tseng, Aleksandra Drelich

et al.

ACS Chemical Biology, Journal Year: 2021, Volume and Issue: 16(4), P. 642 - 650

Published: March 31, 2021

Host-cell cysteine proteases play an essential role in the processing of viral spike protein SARS coronaviruses. K777, irreversible, covalent inactivator that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 infectivity several host cells: Vero E6 (EC50< 74 nM), HeLa/ACE2 (4 Caco-2 (EC90 = 4.3 μM), and A549/ACE2 (<80 nM). Infectivity Calu-3 cells depended on cell line assayed. If Calu-3/2B4 was used, EC50 7 nM, but ATCC without ACE2 enrichment, >10 μM. There no toxicity to any lines at 10–100 μM K777 concentration. Kinetic analysis confirmed a potent inhibitor human cathepsin L, whereas inhibition (papain-like 3CL-like protease) observed. Treatment with propargyl derivative as activity-based probe identified B L intracellular targets this molecule both infected uninfected cells. However, cleavage only carried out by L. This blocked occurred S1 domain protein, different site from previously observed for SARS-CoV-1 protein. These data support hypothesis antiviral activity is mediated through subsequent loss L-mediated processing.

Language: Английский

Citations

107
Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways DOI Creative Commons
Naoko Iwata‐Yoshikawa, Masatoshi Kakizaki,

Nozomi Shiwa-Sudo

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 15, 2022

Abstract In cultured cells, SARS-CoV-2 infects cells via multiple pathways using different host proteases. Recent studies have shown that the furin and TMPRSS2 (furin/TMPRSS2)-dependent pathway plays a minor role in infection of Omicron variant. Here, we confirm uses furin/TMPRSS2-dependent inefficiently enters mainly cathepsin-dependent endocytosis TMPRSS2-expressing VeroE6/TMPRSS2 Calu-3 cells. This is case despite efficient cleavage spike protein Omicron. However, airways TMPRSS2-knockout mice, significantly reduced. We furthermore show propagation mouse-adapted QHmusX strain human clinical isolates Beta Gamma reduced mice. Therefore, variant isn’t an exception vivo, analysis with mice important when evaluating variants. conclusion, this study shows critically for murine airways, including

Language: Английский

Citations

83
Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2 DOI Creative Commons
Bingjie Hu, Jasper Fuk‐Woo Chan, Huan Liu

et al.

Emerging Microbes & Infections, Journal Year: 2022, Volume and Issue: 11(1), P. 2275 - 2287

Published: Aug. 30, 2022

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating variant globally. Omicron BA.1 contains more than 30 mutations spike protein, which contribute to its altered virological features when compared ancestral or previous variants. Recent studies by us others demonstrated that is less dependent on transmembrane serine protease 2 (TMPRSS2), efficient cleavage, fusogenic, adopts an propensity utilize plasma membrane endosomal pathways for virus entry. Ongoing suggest these of are part retained subsequent sublineages. However, exact determinants remain incompletely understood. In this study, we investigated observed characteristics Omicron. By screening individual changes BA.2 spike, identify 69-70 deletion, E484A, H655Y reduced TMPRSS2 usage while 25-27 S375F, T376A result cleavage. Among shared BA.2, S375F reduce spike-mediated fusogenicity. Interestingly, change consistently reduces increases use proteases. keeping with findings, substitution alone entry facilitates WT. Overall, our study identifies key contributes understanding determinant pathogenicity

Language: Английский

Citations

72
Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2 DOI Creative Commons
Manon Venet, Margarida Sá Ribeiro, Élodie Décembre

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 8, 2023

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range by pDCs requires sustained integrin-mediated cell adhesion with infected In turn, restrict viral spread an response directed toward This specialized function enables to efficiently turn-off replication, likely via a local at contact site By exploring pDC in patients, further responsiveness inversely correlates severity disease. The is particularly impaired severe COVID-19 patients. Overall, propose activation essential control SARS-CoV-2-infection. Failure develop could be understand cases COVID-19.

Language: Английский

Citations

42
Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue DOI Creative Commons

Guoli Shi,

Tiansheng Li, Kin Kui Lai

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 30, 2024

Omicron emerged following COVID-19 vaccination campaigns, displaced previous SARS-CoV-2 variants of concern worldwide, and gave rise to lineages that continue spread. Here, we show exhibits increased infectivity in primary adult upper airway tissue relative Delta. Using recombinant forms nasal epithelial cells cultured at the liquid-air interface, mutations unique Spike enable enhanced entry into tissue. Unlike earlier SARS-CoV-2, our findings suggest enters independently serine transmembrane proteases instead relies upon metalloproteinases catalyze membrane fusion. Furthermore, demonstrate this pathway unlocked by enables evasion from constitutive interferon-induced antiviral factors restrict attachment. Therefore, transmissibility exhibited humans may be attributed not only its vaccine-elicited adaptive immunity, but also superior invasion epithelia resistance cell-intrinsic barriers present therein.

Language: Английский

Citations

19