Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection DOI Creative Commons
Martina Severa, Roberta A. Diotti, Marilena P. Etna

et al.

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(9), P. e1009878 - e1009878

Published: Sept. 2, 2021

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell tissue damage associated multi-organ failure. Here, early interaction between immune cells was investigated interrogating vitro human peripheral blood mononuclear (PBMC)-based experimental model. We found that, even absence of productive viral replication, virus mediates vigorous TLR7/8-dependent production both III IFNs cytokines chemokines, known to contribute storm observed COVID-19. Interestingly, we how virus-induced secreted PBMC enhances anti-viral infected lung epithelial cells, thus, inhibiting replication. This released plasmacytoid dendritic (pDC) via ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype inducing surface expression PD-L1 marker, feature producing cells. Coherently what vitro, asymptomatic subjects displayed similar very high serum level induction IFN-stimulated genes PBMC. Conversely, hospitalized with severe COVID-19 display low frequency circulating levels chemokines pro-inflammatory serum. study further shed light on events resulting from occurring confirmed ex vivo. These observations can improve our understanding contribution pDC/type axis regulation state patients.

Language: Английский

Dictionary learning for integrative, multimodal and scalable single-cell analysis DOI Open Access
Yuhan Hao, Tim Stuart, Madeline H. Kowalski

et al.

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(2), P. 293 - 304

Published: May 25, 2023

Language: Английский

Citations

1410
Diverse functional autoantibodies in patients with COVID-19 DOI Creative Commons
Eric Y. Wang, Tianyang Mao, Jon Klein

et al.

Nature, Journal Year: 2021, Volume and Issue: 595(7866), P. 283 - 288

Published: May 19, 2021

Language: Английский

Citations

835
Autophagy in inflammation, infection, and immunometabolism DOI Creative Commons
Vojo Deretić

Immunity, Journal Year: 2021, Volume and Issue: 54(3), P. 437 - 453

Published: March 1, 2021

Language: Английский

Citations

579
Unexplained post-acute infection syndromes DOI Open Access
Jan Choutka,

Viraj Jansari,

Mady Hornig

et al.

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(5), P. 911 - 923

Published: May 1, 2022

Language: Английский

Citations

426
Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19 DOI Creative Commons
Carly G.K. Ziegler, Vincent N. Miao, Anna H. Owings

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(18), P. 4713 - 4733.e22

Published: July 23, 2021

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper symptoms, suggesting potential to constrain viral pathology the nasopharynx. Which cells primarily targets and how influences epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy COVID-19 participants. During COVID-19, we observe expansion of secretory, loss ciliated, epithelial cell repopulation via deuterosomal expansion. In mild moderate express anti-viral/interferon-responsive genes, while in have muted anti-viral responses despite equivalent loads. RNA

Language: Английский

Citations

283
Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1 DOI Creative Commons
Paul Bastard, Elizaveta Orlova, Leila Sozaeva

et al.

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(7)

Published: April 23, 2021

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These were recently reported to account for at least 10% cases life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients 21 kindreds seven countries, aged between 8 48 yr infected SARS-CoV-2 since February 2020. The tested had IFN-α subtypes and/or IFN-ω; one anti-IFN-β another anti-IFN-ε, but none anti-IFN-κ. Strikingly, 19 (86%) hospitalized pneumonia, 15 (68%) admitted an intensive care unit, 11 (50%) who required mechanical ventilation, four (18%) died. Ambulatory disease three (14%) was possibly accounted by prior or early specific interventions. Preexisting IFNs confer very high risk any age.

Language: Английский

Citations

258
Monocytes and Macrophages in COVID-19 DOI Creative Commons
Rainer Knoll, Joachim L. Schultze, Jonas Schulte-Schrepping

et al.

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

Citations

242
The interferon landscape along the respiratory tract impacts the severity of COVID-19 DOI Creative Commons
Benedetta Sposito, Achille Broggi, Laura Pandolfi

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(19), P. 4953 - 4968.e16

Published: Aug. 19, 2021

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role interferons (IFNs) type I (IFN-I) or III (IFN-III) families remains debated. We scrutinized production IFNs along respiratory tract COVID-19 patients and found that high levels IFN-III, to a lesser extent IFN-I, characterize upper airways with viral burden reduced risk severity. Production specific not members denotes mild pathology efficiently drives transcription genes protect against severe acute syndrome 2 (SARS-CoV-2). In contrast, compared subjects other infectious noninfectious lung pathologies, are overrepresented in lower exhibit gene pathways associated increased apoptosis decreased proliferation. Our data demonstrate dynamic SARS-CoV-2-infected show play opposing roles at distinct anatomical sites.

Language: Английский

Citations

238
High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages DOI Creative Commons
Willianne Hoepel, Hung‐Jen Chen, Chiara E. Geyer

et al.

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(596)

Published: May 11, 2021

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation adaptive immune response. Here, we provide evidence that antibodies play a role in worsening at seroconversion. We show early-phase severe acute respiratory distress syndrome 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) serum COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. identified this response is dependent on two antibody features are specific for COVID-19. First, inflammation driven high titers anti-spike IgG, hallmark disease. Second, found IgG from intrinsically more proinflammatory because different glycosylation, particularly low fucosylation, Fc tail. Low fucosylation was normalized few weeks after initial infection SARS-CoV-2, indicating increased antibody-dependent mainly occurs Fcγ receptor (FcγR) IIa and FcγRIII as primary receptors responsible induction key COVID-19-associated cytokines such interleukin-6 tumor necrosis factor. In addition, IgG-activated macrophages can subsequently break pulmonary endothelial barrier integrity induce microvascular thrombosis vitro. Last, demonstrate induced be specifically counteracted fostamatinib, an FDA- EMA-approved therapeutic small-molecule inhibitor Syk kinase.

Language: Английский

Citations

218
Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19 DOI Creative Commons
Monique G.P. van der Wijst, Sara E. Vazquez, George C. Hartoularos

et al.

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

Citations

202