Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

High titers and low fucosylation of early anti-SARS-CoV-2 IgG promote hyper-inflammation by anti-inflammatory macrophages (MIL10)

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

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Homo sapiens

SUBMITTER: Hung-Jen Chen

PROVIDER: E-MTAB-10431 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Publications

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.

Hoepel Willianne W Chen Hung-Jen HJ Geyer Chiara E CE Allahverdiyeva Sona S Manz Xue D XD de Taeye Steven W SW Aman Jurjan J Mes Lynn L Steenhuis Maurice M Griffith Guillermo R GR Bonta Peter I PI Brouwer Philip J M PJM Caniels Tom G TG van der Straten Karlijn K Golebski Korneliusz K Jonkers René E RE Larsen Mads D MD Linty Federica F Nouta Jan J van Roomen Cindy P A A CPAA van Baarle Frank E H P FEHP van Drunen Cornelis M CM Wolbink Gertjan G Vlaar Alexander P J APJ de Bree Godelieve J GJ Sanders Rogier W RW Willemsen Lisa L Neele Annette E AE van de Beek Diederik D Rispens Theo T Wuhrer Manfred M Bogaard Harm Jan HJ van Gils Marit J MJ Vidarsson Gestur G de Winther Menno M den Dunnen Jeroen J

Science translational medicine 20210511 596

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by hu ...[more]

PMID: 33979301

Similar Datasets

Project description:Background. COVID-19-induced neurological disease is a growing concern. Here we provide a comprehensive clinical, molecular, and neuroimaging investigation of patients presenting neurological symptoms to investigate underlying processes. Methods. We performed a detailed systematized clinical, laboratory, and neuroimaging (CT/MRI) data analysis from 35 mild to severe Brazilian COVID-19 hospitalised patients with clinical indications for cerebrospinal fluid (CSF) exam. In patients' CSF, we measured interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and the Alzheimer's disease-associated biomarkers amyloid-beta (Aβ)1-40, Aβ1-42, Tau and pTau181 levels (n=31-35). In addition, CSF proteomics and the search for SARS-CoV-2 spike protein presence using shotgun and targeted multiple reaction monitoring liquid-chromatography/mass-spectrometry were performed (n=16). We further evaluated a 29-cytokine panel in patients’ blood (n=16). An electronic questionnaire was conducted one-year post-hospitalisation (n=19, 63.3%). Findings. COVID-19 patients presented heterogeneous clinical and neurological features, including encephalopathy, encephalitis, and neuromuscular syndromes, despite low pulmonary burden. Patients showed increased circulating cytokines and CSF IL-6 and TNF-α levels compared to controls. Alzheimer’s disease-related biomarkers were unaltered compared to controls. COVID-19 altered CSF proteomic pathways associated to complement and coagulation cascades, immune-inflammatory, metabolism and amyloidosis. We found no traces of spike protein in patients’ CSF. Severe patients presented more pronounced neuroimaging alterations, altered CSF levels of IL-6, Tau, and Aβ-species compared to mild patients. Peripheral inflammation markers correlated with CSF IL-6 and Tau-species levels. Finally, in a one-year post-COVID survey, survivors were not recovered entirely (12/19) and reported confusion or memory/attention deficits (13/19). Interpretation. COVID-19 induces a broad spectrum of neurological presentations associated with changes in central nervous system (CNS) inflammatory and neurodegenerative molecular and structural biomarkers that correlate with systemic inflammation and disease severity. Given that neurological symptoms persist up to one-year post-COVID, our results urge us to investigate whether systemic, and CNS molecular changes are permanent or alleviated so that COVID-19 patients with lingering symptoms are adequately treated.

Dataset Information

High titers and low fucosylation of early anti-SARS-CoV-2 IgG promote hyper-inflammation by anti-inflammatory macrophages (MIL10)

Publications

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets