N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Cell, Год журнала: 2021, Номер 184(9), С. 2332 - 2347.e16

Опубликована: Март 18, 2021

Язык: Английский

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Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Июнь 11, 2021

Abstract The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 exceptionally high level transmissibility extremely broad tissue tropism. However, the underlying molecular mechanism responsible sustaining this degree virulence remains largely unexplored. In article, we review current knowledge crucial information about how attaches on surface host cells through a variety receptors, such as ACE2, neuropilin-1, AXL, antibody–FcγR complexes. We further explain its spike (S) protein undergoes conformational transition from prefusion to postfusion with help proteases like furin, TMPRSS2, cathepsins. then ongoing experimental studies clinical trials antibodies, peptides, or small-molecule compounds anti-SARS-CoV-2 activity, discuss these antiviral therapies targeting host–pathogen interaction could potentially suppress viral attachment, reduce exposure fusion peptide curtail membrane block formation six-helix bundle (6-HB) core. Finally, specter rapidly emerging variants deserves serious broad-spectrum drugs vaccines long-term prevention control COVID-19 future.

Язык: Английский

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Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies

Nature, Год журнала: 2021, Номер 598(7880), С. 342 - 347

Опубликована: Авг. 31, 2021

Язык: Английский

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COVID-19: A review of therapeutic strategies and vaccine candidates

Clinical Immunology, Год журнала: 2020, Номер 222, С. 108634 - 108634

Опубликована: Ноя. 17, 2020

Язык: Английский

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Whole-genome sequencing reveals host factors underlying critical COVID-19

Nature, Год журнала: 2022, Номер 607(7917), С. 97 - 103

Опубликована: Март 7, 2022

Abstract Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics Mortality in Care) study enables comparison genomes from individuals who are critically ill those population controls to find underlying disease mechanisms. Here we use whole-genome sequencing 7,491 compared 48,400 discover and replicate 23 independent variants that significantly predispose COVID-19. We identify 16 new associations, including within genes involved interferon signalling ( IL10RB PLSCR1 ), leucocyte differentiation BCL11A ) blood-type antigen secretor status FUT2 ). Using transcriptome-wide association colocalization infer effect gene expression on severity, evidence implicates multiple genes—including reduced a membrane flippase ATP11A increased mucin MUC1 )—in disease. Mendelian randomization provides support causal roles for myeloid cell adhesion molecules SELE , ICAM5 CD209 coagulation factor F8 all which potentially druggable targets. Our results broadly consistent multi-component model pathophysiology, at least two distinct mechanisms can life-threatening disease: failure control viral replication; an enhanced tendency towards pulmonary inflammation intravascular coagulation. show between cases highly efficient detection therapeutically relevant

Язык: Английский

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Monocytes and Macrophages in COVID-19

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Июль 21, 2021

COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The characterized primarily, but not exclusively, respiratory clinical manifestations ranging from mild common cold symptoms, including cough fever, severe distress multi-organ failure. Macrophages, heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes complex ontogeny present in all mammalian organs, play critical roles developmental, homeostatic host defense processes tissue-dependent plasticity. In case infection, they are responsible for early pathogen recognition, initiation resolution inflammation, as well repair tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, recruited under pathological conditions such infections the affected defend organism against invading pathogens aid efficient inflammation. Given their pivotal function potential danger posed dysregulated hyperinflammation, understanding monocyte macrophage phenotypes key tackling disease's mechanisms. Here, we outline current knowledge on monocytes macrophages homeostasis summarize concepts findings role COVID-19. While blood patients moderate inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized loss HLA-DR expression induction S100 alarmin dominant feature disease. Pulmonary infiltrating inflammatory hyperactivated state resulting detrimental loop pro-inflammatory cytokine release recruitment cytotoxic effector cells thereby exacerbating damage at site infection.

Язык: Английский

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CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2

ACS Central Science, Год журнала: 2021, Номер 7(7), С. 1156 - 1165

Опубликована: Июнь 30, 2021

As the COVID-19 pandemic continues to spread, investigating processes underlying interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report identification CD209L/L-SIGN related protein CD209/DC-SIGN as receptors capable mediating entry into human cells. Immunofluorescence staining tissues revealed prominent expression CD209L in lung kidney epithelia endothelia. Multiple biochemical assays using a purified recombinant spike receptor-binding domain (S-RBD) or S1 encompassing both N termal RBD ectopically expressed CD209 that interact with S-RBD. contains two N-glycosylation sequons, at sites N92 N361, but determined only site occupied. Removal this enhances binding S-RBD CD209L. also interacts ACE2, suggesting role for heterodimerization ACE2 infection cell types where are present. Furthermore, demonstrate endothelial cells permissive infection, interference activity by knockdown strategy soluble inhibits virus entry. Our observations serve alternative disease-relevant types, including vascular system. This property particularly important has low absent may have implications antiviral drug development.

Язык: Английский

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Cellular host factors for SARS-CoV-2 infection

Nature Microbiology, Год журнала: 2021, Номер 6(10), С. 1219 - 1232

Опубликована: Сен. 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.

Язык: Английский

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Cell entry by SARS-CoV-2

Trends in Biochemical Sciences, Год журнала: 2021, Номер 46(10), С. 848 - 860

Опубликована: Июнь 7, 2021

Both severe acute respiratory syndrome virus 2 (SARS-CoV-2) and SARS-CoV mainly invade human lungs, although increasing evidence shows that SARS-CoV-2 can also infect many other tissues to develop systematic infection multiple organ damage, hijack T cells directly paralyze host immunity.Angiotensin-converting enzyme (ACE2) is the major receptor for a crucial determinant cross-species transmission of virus; establish infections in panel domestic or wild animals via their ACE2 orthologs.Several proteins non-protein molecules have been found interact with S protein serve as potential alternative/auxiliary attachment receptors/coreceptors facilitate entry into specific types cells.Membrane fusion requires two proteolytic events by proteases, S1/S2 boundary harbors polybasic insertion expands spectrum available proteases thus tropism different tissues. Severe invades interacting receptors/coreceptors, well cofactors, its spike (S) further mediates between viral cellular membranes. The membrane protein, angiotensin-converting (ACE2), transmission. In addition, some auxiliary receptors cofactors are involved expand host/tissue SARS-CoV-2. After engagement, required cleave trigger fusogenic activity. Here we discuss recent advances understanding molecular during which will contribute developing vaccines therapeutics. late 2019 novel coronavirus named emerged humans, causes disease (COVID-19) [1.Coronaviridae Study Group International Committee on Taxonomy Viruses species syndrome-related coronavirus: classifying 2019-nCoV naming it SARS-CoV-2.Nat. Microbiol. 2020; 5: 536-544Crossref PubMed Scopus (2460) Google Scholar, 2.Zhou P. et al.A pneumonia outbreak associated new probable bat origin.Nature. 579: 270-273Crossref (7642) 3.Zhu N. from patients China, 2019.New Engl. J. Med. 382: 727-733Crossref (9884) 4.Wu F. China.Nature. 265-269Crossref (3658) Scholar]. This has rapidly developed worldwide pandemic resulted more than 0.1 billion confirmed cases 23 May 2021, including ~3.5 million deaths (www.who.int/emergencies/diseases/novel-coronavirus-2019). seventh human-infecting (HCoV) identified so far (Box 1), most similar 2002 [4.Wu Scholar,5.Zhong N.S. al.Epidemiology cause (SARS) Guangdong, People's Republic February, 2003.Lancet. 2003; 362: 1353-1358Abstract Full Text PDF (732) However, exhibits higher efficiency (see Glossary) compared HCoVs [6.Madewell Z.J. al.Household SARS-CoV-2: review meta-analysis.JAMA Netw. Open. 3e2031756Crossref (86) Scholar], relatively lower mortality rate Middle East (MERS-CoV) 7.Liu Z. al.The assessment latent period asymptomatic carriers infection.Int. Infect. Dis. 99: 325-327Abstract (12) 8.Zumla A. al.Middle syndrome.Lancet. 2015; 386: 995-1007Abstract (589) Although several candidate being distributed countries, global situation under control. It very urgent promote vaccination among populations effective therapeutics.Box 1Coronaviruses related epidemics/pandemicsCoronaviruses group enveloped viruses whose surface decorated proteins, resulting crown-shaped morphology. genome coronaviruses single-stranded positive-sense RNA an mRNA translation [11.V'Kovski al.Coronavirus biology replication: implications Rev. 19: 155-170Crossref (0) Coronaviruses belong order Nidovirales, family Coronaviridae, classified Orthocoronavirinae Letovirinae subfamilies. All (HCoVs) included subfamily Orthocoronavirinae, divided four genera, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, Deltacoronavirus [9.Siddell S.G. al.Coronaviridae.Intervirology. 1983; 20: 181-189Crossref (55) So far, total seven identified. Among them, 229E, NL63, OC43, HKU1 commonly around world, mild symptoms such common cold fever. three, SARS-CoV, MERS-CoV, SARS-CoV-2, categorized highly pathogenic caused epidemics/pandemics countries.The first 229E reported 1960s (Figure I) [107.Tyrrell D.A. Bynoe M.L. Cultivation type common-cold cultures.Br. 1965; 1: 1467-1470Crossref Scholar,108.Hamre D. Procknow J.J. A isolated tract.Proc. Soc. Exp. Biol. 1966; 121: 190-193Crossref They often detected at same time usually do not lead symptoms. 2004 NL63 was discovered baby bronchiolitis Netherlands [109.van der Hoek L. al.Identification coronavirus.Nat. 2004; 10: 368-373Crossref (1155) year later Hong Kong, China elderly patient [110.Woo P.C. al.Characterization complete sequence coronavirus, HKU1, pneumonia.J. Virol. 2005; 79: 884-895Crossref (920) Since then, this world. case [5.Zhong epidemic spread over 30 countries ended 2003, 8000 infection, almost 800 deaths. MERS-CoV Saudi Arabia 2012 Asian [111.Zaki A.M. al.Isolation man Arabia.New 2012; 367: 1814-1820Crossref (2963) 2500 reported, ~850 died MERS-related disease, highest fatality (~35%) all HCoVs. were Wuhan, [3.Zhu led unprecedented ongoing affects As confirmed, 3.5 death cases. much those but seems be efficient populations. three thought originate animals, potentially natural host, bats [2.Zhou Scholar,112.Hu B. al.Bat origin coronaviruses.Virol. 12: 221Crossref (181) countries. large ~30 000 nt encodes classes proteins: polyproteins, pp1a pp1ab, cleaved 16 non-structural (NSPs) synthesis (and probably functions); structural (the spike, envelope, membrane, nucleocapsid proteins) essential assembly; nine accessory counteract immunity [10.Fehr A.R. Perlman S. Coronaviruses: overview replication pathogenesis.Methods Mol. 1282: 1-23Crossref Scholar,11.V'Kovski Viral step one important processes life cycle, key target process executed envelope recognizes cell allow released cytoplasm [12.Belouzard al.Mechanisms mediated protein.Viruses. 4: 1011-1033Crossref review, summarize functional studies entry, emphasis protein-mediated binding processes, factors coreceptors 1). An average 30–60 trimers protrude virion, distance 15 nm each [13.Yao H. al.Molecular architecture virus.Cell. 183: 730-738Abstract (139) 14.Ke al.Structures distributions intact virions.Nature. 588: 498-502Crossref (170) 15.Turonova al.In situ analysis reveals flexibility hinges.Science. 370: 203-208Crossref (135) Each trimeric ~10 length long helix stalk hinge allows adopt orientations [14.Ke Scholar,15.Turonova typical class I largest machine containing 1200 amino acid residues. During process, undergoes cleavage S1 S2 subunits remain assemble heterodimer 2) [16.Duan glycoprotein biosynthesis, structure, function, antigenicity: design spike-based vaccine immunogens.Front. Immunol. 11576622Crossref (46) Scholar,17.Walls A.C. al.Structure, antigenicity glycoprotein.Cell. 181: 281-292Abstract (2842) subunit N-terminal domain (NTD) C-terminal (CTD), latter responsible termed receptor-binding (RBD) [17.Walls 18.Wrapp al.Cryo-EM structure prefusion conformation.Science. 1260-1263Crossref (19) 19.Wang Q.H. al.Structural basis using ACE2.Cell. 894-904Abstract (890) 20.Lan al.Structure bound receptor.Nature. 581: 215-220Crossref (1531) 21.Shang recognition SARS-CoV-2.Nature. 221-224Crossref (1165) portion consists upstream (UH) region, peptide (FP), heptad repeat 1 (HR1), central (CD), (HR2), transmembrane (TM), cytoplasmic tail (CP) 2A,B). contrast FP located immediate N terminus subunit. Instead, shielded UH therefore second event expose [22.Matsuyama Protease-dependent mechanism coronaviruses.Uirusu. 2011; 61 (article Japanese): 109-116Crossref (1) Scholar,23.Walls al.Tectonic conformational changes fusion.Proc. Natl. Acad. Sci. U. 2017; 114: 11157-11162Crossref (218) Proteolysis S2′ site remove activating capacity triggers irreversible initiate [24.Fan X. post-fusion glycoprotein.Nat. Commun. 11: 3618Crossref (41) 25.Hoffmann M. al.SARS-CoV-2 depends TMPRSS2 blocked clinically proven protease inhibitor.Cell. 271-280Abstract (6278) 26.Cai Y. al.Distinct states protein.Science. 369: 1586-1592Crossref (207) Soon after outbreak, groups promptly 2002–2003 Scholar,25.Hoffmann Scholar] 3). 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Adv. 7eabe5575Crossref (17) 35.Zhou T.Q. without reveal pH-dependent switch endosomal positioning domains.Cell Host Microbe. 28: 867-879Abstract snapshots enable deduction scenario 4). conformations state buried adjacent protomer (closed conformation) exposed access (open (Figures 2C 4A), known Scholar,36.Yuan glycoproteins dynamic domains.Nat. 8: 15092Crossref (342) within synchronized, implying asymmetric interactions receptor. study open transition closed make them accessible 4B) Therefore, 1–3 copies depending conformation individual Scholar,35.Zhou modulates local disrupt core, involves salt bridge contributed residue D614 Progressive dissociation head stalk, facilitates activation proteolysis 4C) Of note, variant harboring D614G substitution Europe mid-2020. mutation makes RB

Язык: Английский

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Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells?

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(3), С. 992 - 992

Опубликована: Янв. 20, 2021

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from viral surface is densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) mediate host cell entry. However, studies have reported susceptibility in intra- and extrapulmonary immune non-immune cells lacking ACE2, suggesting that S protein may exploit additional receptors infection. Studies demonstrated interactions between innate system, including C-lectin type (CLR), toll-like (TLR) neuropilin-1 (NRP1), receptor glucose regulated 78 (GRP78). Recognition carbohydrate moieties clustered on drive receptor-dependent internalization, accentuate immunopathological inflammation, allow systemic spread infection, independent ACE2. Furthermore, targeting TLRs, CLRs, other (Ezrin dipeptidyl peptidase-4) do not directly engage SARS-CoV-2 but contribute augmented anti-viral immunity clearance, represent therapeutic targets against COVID-19.

Язык: Английский

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