Mechanisms of SARS-CoV-2 entry into cells

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 23(1), С. 3 - 20

Опубликована: Окт. 5, 2021

Язык: Английский

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FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

Nature, Год журнала: 2022, Номер 606(7914), С. 576 - 584

Опубликована: Апрель 6, 2022

Язык: Английский

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The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Nature Neuroscience, Год журнала: 2021, Номер 24(11), С. 1522 - 1533

Опубликована: Окт. 21, 2021

Abstract Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in of patients with COVID-19 elucidate potential mechanisms underlying the vascular pathology. In brains severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals animal models, found an increased number empty basement membrane tubes, so-called string representing remnants lost capillaries. We obtained evidence that brain endothelial cells are infected main protease SARS-CoV-2 (M pro ) cleaves NEMO, essential modulator nuclear factor-κB. By ablating M induces death human occurrence mice. Deletion receptor-interacting protein kinase (RIPK) 3, a mediator regulated cell death, blocks vessel rarefaction disruption blood–brain barrier due to NEMO ablation. Importantly, pharmacological inhibitor RIPK signaling prevented -induced microvascular Our data suggest as therapeutic target treat neuropathology COVID-19.

Язык: Английский

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Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(35)

Опубликована: Авг. 11, 2022

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum cerebral impact acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranging from alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to damage confirmed brain tissue samples extracted orbitofrontal region (via endonasal transethmoidal access) who died COVID-19. In an independent cohort 26 COVID-19, we used histopathological signs a guide for possible SARS-CoV-2 infection found that among 5 exhibited those signs, all them had genetic material virus brain. Brain these five patients also foci replication, particularly astrocytes. Supporting hypothesis astrocyte neural stem cell-derived human astrocytes vitro are susceptible through noncanonical mechanism involves spike-NRP1 interaction. SARS-CoV-2-infected manifested changes energy metabolism key proteins metabolites fuel neurons, well biogenesis neurotransmitters. Moreover, elicits secretory phenotype reduces neuronal viability. Our data support model which reaches brain, infects astrocytes, consequently, leads death or dysfunction. These deregulated processes could contribute structural functional seen brains patients.

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). ACE2, carboxypeptidase cleaves polypeptides renin/angiotensin system, cardiac function widely expressed various organs, suggesting [27.Kuba K. al.Multiple functions relevance cardiovascular diseases.Circ. 2013; 77: 301-308Crossref (96) Scholar,28.Yan R. full-length ACE2.Science. 1444-1448Crossref (1720) RBDs share high degree identity (74%) exhibit interaction profiles [19.Wang substitutions residues RBD atomic contacts affinity (~fourfold difference) 3C,D) property may human-to-human Scholar,7.Liu orthologs mammals cats, dogs, pigs, camels, horses, pangolins, bats, indicating SARS-CoV2 likely broad [29.Rodrigues al.Insights modeling.PLoS Comput. 16e1008449Crossref (5) Some closely pangolins Scholar,30.Xiao K.P. SARS-CoV-2-related Malayan pangolins.Nature. 583: 286-289Crossref (208) Two shown wide range bind mediate pseudotyped viruses, S-binding interface displays significant diversity 3E,F) [31.Liu al.Cross-species ACE2.Proc. 2021; 118e2020216118Crossref (2) Scholar,32.Wu al.Broad cat ACE2.Cell Discov. 6: 68Crossref (26) These findings strongly imply experienced spillover adaptation diverse determinants enabled host-jump across intermediate hosts finally allowed humans. Cryogenic electron microscopy (cryo-EM) determined structures conformations, both before Scholar,18.Wrapp Scholar,26.Cai complex [33.Benton D.J. al.Receptor priming fusion.Nature. 327-330Crossref (119) 34.Xu C. al.Conformational dynamics revealed cryo-EM.Sci. 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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Interactions of SARS-CoV-2 with the Blood–Brain Barrier

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(5), С. 2681 - 2681

Опубликована: Март 6, 2021

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is critical interface regulates entry circulating molecules into the CNS, and regulated by signals arise from brain blood compartments. In this review, we discuss mechanisms which SARS-CoV-2 interactions with BBB may contribute to dysfunction associated disease 2019 (COVID-19), caused SARS-CoV-2. We consider aspects peripheral disease, such hypoxia systemic inflammatory response syndrome/cytokine storm, well CNS infection viral brain. also contribution risk factors for developing COVID-19 could increase or otherwise damage

Язык: Английский

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SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro

Frontiers in Cellular and Infection Microbiology, Год журнала: 2021, Номер 11

Опубликована: Июль 6, 2021

SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema hemorrhage. In addition the lung, cytokine storm-induced cascade also affects other organs. infection-related inflammation is characterized by endotheliopathy in Whether causes directly infecting endothelial cells not known focus of present study. We observed 1) co-localization with cell marker CD31 lungs SARS-CoV-2-infected mice expressing hACE2 intranasal delivery adenovirus 5-hACE2 (Ad5-hACE2 mice) non-human primates at both protein RNA levels, 2) proteins immunogold labeling electron microscopic analysis. detected autopsied tissue obtained from patients who died severe COVID-19. Comparative analysis sequencing data infected Ad5-hACE2 Ad5-empty (control) revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation dysfunction. Further, we showed that infects mature mouse aortic (AoECs) were activated performing an sprouting assay prior exposure SARS-CoV-2. This was demonstrated CD34 immunostaining detection viral particles studies. Moreover, AoECs became positive ACE-2 but quiescent AoECs. Together, our results indicate pneumocytes, vivo ex vivo, which may contribute cardiovascular complications infection, multipleorgan failure.

Язык: Английский

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Impact of virus genetic variability and host immunity for the success of COVID-19 vaccines

Biomedicine & Pharmacotherapy, Год журнала: 2021, Номер 136, С. 111272 - 111272

Опубликована: Янв. 13, 2021

Coronavirus disease 19 (COVID-19) continues to challenge most scientists in the search of an effective way either prevent infection or avoid spreading disease. As result global efforts some advances have been reached and we are more prepared today than were at beginning pandemic, however not enough stop transmission, many questions remain unanswered. The possibility reinfection recovered individuals, duration immunity, impact SARS-CoV-2 mutations as well degree protection that a potential vaccine could issues under debate. A number vaccines development using different platforms clinical trials ongoing countries, but even if they licensed it will need time until reach definite conclusion about their real safety efficacy. Herein discuss strategies used COVID-19 vaccines, underlying type immune response may elicit, consequences new generation sub-strains challenges for efficacy scenario postpandemic.

Язык: Английский

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A physical wiring diagram for the human immune system

Nature, Год журнала: 2022, Номер 608(7922), С. 397 - 404

Опубликована: Авг. 3, 2022

The human immune system is composed of a distributed network cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes

Язык: Английский

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