Local and systemic responses to SARS-CoV-2 infection in children and adults

Nature, Journal Year: 2021, Volume and Issue: 602(7896), P. 321 - 327

Published: Dec. 22, 2021

It is not fully understood why COVID-19 typically milder in children

Language: Английский

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Monocytes and Macrophages in COVID-19

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: July 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.

Language: Английский

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Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Jan. 14, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious virus which responsible for the disease 2019 (COVID-19) pandemic. It increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms many months after infection, condition referred to as "long COVID", post-acute sequelae of COVID-19 (PASC), syndrome, or post condition. However, despite plethora research on relatively little known about molecular underpinnings these long-term effects.We have undertaken an integrated analysis immune responses in blood at transcriptional, cellular, and serological level 12, 16, 24 weeks post-infection (wpi) 69 patients recovering mild, moderate, severe, critical comparison healthy uninfected controls. Twenty-one were long COVID clinic > 50% reported ongoing more than 6 post-infection.Anti-Spike anti-RBD IgG largely stable up wpi correlated with severity. Deep immunophenotyping revealed significant differences multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) adaptive populations (T helper, T follicular regulatory cells) convalescent individuals compared controls, most strongly evident 12 16 wpi. RNA sequencing perturbations gene expression convalescents until least post-infection. We also uncovered transcriptome not.Variation rate recovery infection cellular transcriptional may explain persistence associated some individuals.

Language: Английский

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Mapping the developing human immune system across organs

Science, Journal Year: 2022, Volume and Issue: 376(6597)

Published: May 12, 2022

Single-cell genomics studies have decoded the immune cell composition of several human prenatal organs but were limited in describing developing system as a distributed network across tissues. We profiled nine tissues combining single-cell RNA sequencing, antigen-receptor and spatial transcriptomics to reconstruct system. This revealed late acquisition immune-effector functions by myeloid lymphoid subsets maturation monocytes T cells before peripheral tissue seeding. Moreover, we uncovered system-wide blood development beyond primary hematopoietic organs, characterized B1 cells, shed light on origin unconventional cells. Our atlas provides both valuable data resources biological insights that will facilitate engineering, regenerative medicine, disease understanding.

Language: Английский

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Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Language: Английский

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Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(612)

Published: Aug. 24, 2021

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the caused by severe acute respiratory syndrome 2 (SARS-CoV-2). However, prevalence of these antibodies, their longitudinal dynamics across severity scale, and functional effects on circulating leukocytes remain unknown. Here, 284 COVID-19, we IFN–specific peripheral blood samples from 19% 6% disease. We no IFN individuals moderate Longitudinal profiling over 600,000 mononuclear cells using multiplexed single-cell epitope transcriptome sequencing 54 COVID-19 26 non–COVID-19 controls revealed a lack IFN–stimulated gene (ISG-I) responses myeloid This was especially evident dendritic cell populations isolated producing autoantibodies. Moreover, elevated expression inhibitory receptor leukocyte-associated immunoglobulin-like 1 (LAIR1) surface monocytes early course. LAIR1 is inversely correlated ISG-I response but not expressed healthy controls. The deficient observed without supports unifying model for pathogenesis involving suppression through convergent mechanisms.

Language: Английский

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Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19

Immunity, Journal Year: 2021, Volume and Issue: 54(11), P. 2650 - 2669.e14

Published: Sept. 4, 2021

Language: Английский

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Complement activation induces excessive T cell cytotoxicity in severe COVID-19

Cell, Journal Year: 2021, Volume and Issue: 185(3), P. 493 - 512.e25

Published: Dec. 28, 2021

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, it remains unclear whether T cells contribute disease pathology. Here, we combined single-cell transcriptomics proteomics with mechanistic studies assess pathogenic cell functions inducing signals. We identified highly activated CD16

Language: Английский

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Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19

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

Published: Jan. 21, 2022

Abstract Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, signatures associated with immunopathology poorly understood. Here we use multi-omics single-cell analysis to probe dynamic hospitalized patients stable or progressive course of COVID-19, explore V(D)J repertoires, and assess cellular effects tocilizumab. Coordinated profiling gene expression cell lineage protein markers shows that S100A hi /HLA-DR lo classical monocytes activated LAG-3 T cells hallmarks disease highlights abnormal MHC-II/LAG-3 interaction on myeloid cells, respectively. We also find skewed receptor repertories expanded effector CD8 + clones, unmutated IGHG B mutated clones somatic hypermutation frequency over time. In conclusion, our in-depth reveals dyssynchrony innate adaptive

Language: Английский

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Impact of the Human Cell Atlas on medicine

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(12), P. 2486 - 2496

Published: Dec. 1, 2022

Language: Английский

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