Multiple early factors anticipate post-acute COVID-19 sequelae

Cell, Год журнала: 2022, Номер 185(5), С. 881 - 895.e20

Опубликована: Янв. 25, 2022

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation 309 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data patient-reported symptoms. resolved four PASC-anticipating at the time diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, specific auto-antibodies. In gastrointestinal PASC, SARS-CoV-2-specific CMV-specific CD8+ T cells exhibited unique dynamics during recovery COVID-19. Analysis symptom-associated immunological signatures revealed coordinated immunity polarization into endotypes, exhibiting divergent acute severity PASC. find that between diminish over time, leading distinct convalescent immune states. Detectability most emphasizes importance early disease measurements understanding emergent chronic conditions suggests treatment strategies.

Язык: Английский

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Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

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

Опубликована: Март 27, 2021

To discover new drugs to combat COVID-19, an understanding of the molecular basis SARS-CoV-2 infection is urgently needed. Here, for first time, we report crucial role cathepsin L (CTSL) in patients with COVID-19. The circulating level CTSL was elevated after and positively correlated disease course severity. Correspondingly, pseudovirus increased expression human cells vitro ACE2 transgenic mice vivo, while overexpression, turn, enhanced cells. functionally cleaved spike protein virus entry, as evidenced by overexpression knockdown application inhibitor vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited activity prevented both Therefore, promising target anti-COVID-19 drug development.

Язык: Английский

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Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike

Cell, Год журнала: 2022, Номер 185(12), С. 2103 - 2115.e19

Опубликована: Май 2, 2022

Soon after the emergence and global spread of SARS-CoV-2 Omicron lineage BA.1, another lineage, BA.2, began outcompeting BA.1. The results statistical analysis showed that effective reproduction number BA.2 is 1.4-fold higher than Neutralization experiments revealed immunity induced by COVID vaccines widely administered to human populations not against similar antigenicity notably different from Cell culture spike confers replication efficacy in nasal epithelial cells more efficient mediating syncytia formation BA.1 spike. Furthermore, infection using hamsters indicated spike-bearing virus pathogenic virus. Altogether, our multiscale investigations suggest risk health potentially

Язык: Английский

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Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?

Journal of Virology, Год журнала: 2022, Номер 96(6)

Опубликована: Фев. 28, 2022

Emerging strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent disease 2019 (COVID-19) pandemic, that show increased transmission fitness and/or immune evasion are classified as "variants concern" (VOCs). Recently, a SARS-CoV-2 variant first identified in November 2021 South Africa has been recognized fifth VOC, termed "Omicron." What makes this VOC so alarming is high number changes, especially viral Spike protein, and accumulating evidence for efficiency escape from neutralizing antibodies. In an amazingly short time, Omicron outcompeted previously dominating Delta VOC. However, it seems overall less pathogenic than other VOCs. Here, we provide overview mutations genome resulting changes proteins compared to discuss their potential functional consequences.

Язык: Английский

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The Mechanism and Consequences of SARS-CoV-2 Spike-Mediated Fusion and Syncytia Formation

Journal of Molecular Biology, Год журнала: 2021, Номер 434(6), С. 167280 - 167280

Опубликована: Окт. 1, 2021

Язык: Английский

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Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

Circulation, Год журнала: 2022, Номер 145(16), С. 1205 - 1217

Опубликована: Март 18, 2022

Background: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. Methods: We investigated the observational and associations 90 cardiovascular proteins, were measured using affinity-based proteomic assays. First, we estimated incident heart by means fixed-effect meta-analysis 4 population-based studies, composed total 3019 participants 732 HF events. effects HF-associated then Mendelian randomization, cis -protein quantitative loci instruments identified from genomewide association studies in more than 30 000 individuals. To improve precision estimates, implemented randomization model that accounted linkage disequilibrium between tested robustness estimates through multiverse sensitivity analysis included up 120 combinations instrument selection parameters models per protein. druggability candidate was surveyed, mechanism action potential on-target side explored cross-trait analysis. Results: Forty-four ninety positively associated risk ( P <6.0×10 –4 ). Among these, 8 had robust analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) KIM-1 (kidney injury molecule 1) HF, whereas ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein CTSL1 (cathepsin L1), FGF-23 (fibroblast growth 23), MMP-12 (matrix metalloproteinase-12) protective. Therapeutics targeting currently under evaluation clinical trials, all remaining considered druggable, except KIM-1. Conclusions: 44 circulating showed relationship 7 including adrenomedullin, represents particularly promising drug target. Our approach demonstrates tractable roadmap triangulation population genomic data prioritization targets complex human diseases.

Язык: Английский

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A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells

ACS Chemical Biology, Год журнала: 2021, Номер 16(4), С. 642 - 650

Опубликована: Март 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.

Язык: Английский

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Characterization of SARS-CoV-2 Omicron BA.4 and BA.5 isolates in rodents

Nature, Год журнала: 2022, Номер 612(7940), С. 540 - 545

Опубликована: Ноя. 2, 2022

Язык: Английский

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SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages

Science Translational Medicine, Год журнала: 2022, Номер 14(674)

Опубликована: Сен. 22, 2022

Obesity, characterized by chronic low-grade inflammation of the adipose tissue, is associated with adverse coronavirus disease 2019 (COVID-19) outcomes, yet underlying mechanism unknown. To explore whether severe acute respiratory syndrome 2 (SARS-CoV-2) infection tissue contributes to pathogenesis, we evaluated COVID-19 autopsy cases and deeply profiled response SARS-CoV-2 in vitro. In cases, identified RNA adipocytes an inflammatory infiltrate. We two distinct cellular targets infection: a subset tissue-resident macrophages. Mature were permissive infection; although macrophages abortively infected, initiated responses within both infected bystander preadipocytes. These data suggest that could contribute severity through replication virus induction local systemic driven

Язык: Английский

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Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies

Cell Discovery, Год журнала: 2022, Номер 8(1)

Опубликована: Июнь 6, 2022

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage by host proteases essential viral infection. Here, we discovered that contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 CS-2). Both are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed CTSL promoted to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating membrane fusion. We confirmed during infection emerged variants (including recently Omicron variant) pseudovirus (PsV) experiment. Furthermore, found CTSL-specific inhibitors not only blocked PsV/live virus in cells but also reduced live ex vivo lung tissues both human donors ACE2-transgenic mice. Finally, showed exhibited excellent In effects prevent work demonstrated inhibition a promising approach development future mutation-resistant therapy.

Язык: Английский

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