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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Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

Acta Pharmacologica Sinica, Год журнала: 2022, Номер 44(4), С. 695 - 709

Опубликована: Окт. 17, 2022

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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SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1716 - 1716

Опубликована: Фев. 2, 2022

The review aims to consolidate research findings on the molecular mechanisms and virulence pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome 2 (SARS-CoV-2), their relevance four typical stages in development viral infection. These are invasion; primary blockade antiviral innate immunity; engagement virus’s protection against factors adaptive acute, long-term complications COVID-19. invasion stage entails recognition spike protein (S) SARS-CoV-2 target cell receptors, namely, main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, potential alternative receptors. presence a diverse repertoire receptors allows infect various types cells, including those not expressing ACE2. During second stage, majority polyfunctional structural, non-structural, extra proteins synthesizes infected cells involved blockage immunity. A high degree redundancy systemic action characterizing these pathogenic overcome at initial invasion. third includes passive active virus from immunity, overcoming barrier function focus inflammation, generalization body. fourth is associated with deployment variants SARS-CoV-2’s ability induce autoimmune autoinflammatory pathways tissue both immunosuppressive hyperergic inflammation critical this

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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Host genetic factors determining COVID-19 susceptibility and severity

EBioMedicine, Год журнала: 2021, Номер 72, С. 103629 - 103629

Опубликована: Окт. 1, 2021

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic severe courses of with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI pre-existing comorbidities. Ethnicity is also relevant susceptibility severity. Host genetic predisposition now increasingly recognized whole genome candidate gene association studies regarding have been performed. Several common rare variants in genes related inflammation or immune responses identified. We summarize research on host genetics compile associated discuss that should be investigated further understand such associations provide insights pathogenesis, risk classification, therapy response, precision medicine, drug repurposing.

Язык: Английский

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Endothelial cells are not productively infected by SARS‐CoV‐2

Clinical & Translational Immunology, Год журнала: 2021, Номер 10(10)

Опубликована: Янв. 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

Язык: Английский

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Immune response in COVID-19: what is next?

Cell Death and Differentiation, Год журнала: 2022, Номер 29(6), С. 1107 - 1122

Опубликована: Май 17, 2022

Abstract The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle quality in unprecedented ways. A better understanding of immunity its regulation response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here various virus mutations evolving manifestations along with alterations immune responses specific focuses innate response, neutrophil extracellular traps, humoral immunity, cellular immunity. Different types vaccines were compared analyzed based their unique properties elicit Various therapeutic strategies such as antibody, anti-viral medications inflammation control discussed. We predict that available continuously emerging new technologies, powerful administration schedules, effective public health measures, COVID-19 will be under near future.

Язык: Английский

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Extracellular vimentin is an attachment factor that facilitates SARS-CoV-2 entry into human endothelial cells

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(6)

Опубликована: Янв. 25, 2022

SARS-CoV-2 entry into host cells is a crucial step for virus tropism, transmission, and pathogenesis. Angiotensin-converting enzyme 2 (ACE2) has been identified as the primary receptor SARS-CoV-2; however, possible involvement of other cellular components in viral not yet fully elucidated. Here we describe identification vimentin (VIM), an intermediate filament protein widely expressed mesenchymal origin, important attachment factor on human endothelial cells. Using liquid chromatography-tandem mass spectrometry, VIM that binds to spike (S) protein. We showed S-protein binding domain (RBD) sufficient interaction with VIM. Further analysis revealed extracellular facilitates infection, determined by assays performed pseudotyped viruses expressing S infectious SARS-CoV-2. Coexpression ACE2 increased HEK-293 cells, shRNA-mediated knockdown significantly reduced infection Moreover, incubation A549 purified SARS-CoV-2-S entry. CR3022 antibody, which recognizes distinct epitope SARS-CoV-2-S-RBD without interfering ACE2, inhibited CoV-2 S-RBD, neutralized suggesting key role This work provides insight pathogenesis COVID-19 linked vascular system, implications development therapeutics vaccines.

Язык: Английский

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Immune regulatory networks coordinated by glycans and glycan-binding proteins in autoimmunity and infection

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(10), С. 1101 - 1113

Опубликована: Авг. 15, 2023

Abstract The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous exogenous insults. Disruption these safeguard homeostatic mechanisms can lead to unpredictable inflammatory autoimmune responses, whereas deficiency pathways may orchestrate immunosuppressive programs contribute perpetuate chronic infections, but also influence cancer development progression. Glycans have emerged as essential components circuits, acting fine-tuners immunological potential molecular targets for manipulation tolerance activation in a wide range pathologic settings. Cell surface glycans, present cells, tissues the extracellular matrix, been proposed serve “self-associated patterns” store structurally relevant biological data. responsibility deciphering this information relies on different families glycan-binding proteins (including galectins, siglecs C-type lectins) which, upon recognition specific carbohydrate structures, recalibrate magnitude, nature fate responses. This process tightly regulated diversity glycan structures establishment multivalent interactions cell receptors matrix. Here we review spatiotemporal regulation selected glycan-modifying processes including mannosylation, complex N -glycan branching, core 2 O elongation, LacNAc extension, well terminal sialylation fucosylation. Moreover, illustrate examples highlight contribution control their integration with canonical tolerogenic pathways. Finally, discuss power glycans source immunomodulatory signals could be leveraged treatment inflammation infection.

Язык: Английский

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