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Next generation sequencing transcriptome analysis of patient-derived macrophages after SARS-CoV-2 mRNA vaccination

ABSTRACT: Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Recently we could show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals (Theobald et al. EMBO Mol Med. 2021). Further analysis revealed that SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling. In this project we want to focus on novel mRNA vaccines, which are exploiting S-protein driven immunogenicity for protection against SARS-CoV-2. Transcriptome analyses of macrophages might reveal differences in innate immune-associated pathways between vaccinated and unvaccinated individuals after prime-boost. Thus, our project could help to gain a better understanding of vaccine-induced immunity including underlying molecular mechanisms in the interaction of the innate and adaptive immune system after mRNA-based SARS-CoV-2 vaccination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200274 | GEO | 2022/05/02

REPOSITORIES: GEO

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Next generation sequencing transcriptome analysis of patient-derived macrophages stimulated with SARS-CoV-2 protein

Project description:Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. Furthermore, longitudinal analyses reveal robust S-protein driven inflammasome activation in macrophages isolated from convalescent COVID-19 patients, which correlates with distinct epigenetic and gene-expression signatures suggesting innate immune memory after recovery from COVID-19. Importantly, we show that S-protein driven IL-1β secretion from patient-derived macrophages requires non-specific monocyte pre-activation in vivo to trigger NLRP3-inflammasome signaling. Our findings reveal that SARS-CoV-2 infection causes profound and long-lived re-programming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.

2021-06-07 | GSE173488 | GEO

Linear epitope-specific IgG responses to SARS-CoV-2 and related human coronaviruses in human COVID-19 convalescent sera

Project description:The on-going COVID-19 pandemic requires a deeper understanding of the long-term antibody responses that persist following SARS-CoV-2 infection. To that end, we determined epitope-specific IgG antibody responses in COVID-19 convalescent sera collected at 5 months post-diagnosis and compared that to sera from naïve individuals. Each serum sample was reacted with a high-density peptide microarray representing the complete proteome of SARS-CoV-2 as 15 mer peptides with 11 amino acid overlap and homologs of spike glycoprotein, nucleoprotein, membrane protein, and envelope small membrane protein from related human coronaviruses. Binding signatures were compared between COVID-19 convalescent patients and naïve individuals using the web service tool EPIphany.

2022-02-05 | E-MTAB-10740 | biostudies-arrayexpress

Single-Cell RNA Sequencing to Decipher the Immunogenicity of ChAdOx1 nCoV-19/AZD1222 and mRNA-1273 Vaccines in Patients with Autoimmune Rheumatic Diseases

Project description:Objectives: To investigate the differences in efficacy and safety between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna), and evaluate the impact of anti-rheumatic medications on immunogenicity in patients with autoimmune rheumatic diseases (AIRD). Methods: From September 16 to November 15, 2021, we consecutively enrolled participants aged≥20 years with AIRD who received COVID-19 vaccination. The level of serum IgG antibodies to the SARS-Cov-2 receptor-binding domain on the spike protein S1 subunit was quantified by electrochemiluminescence immunoassay at 4-6 weeks after vaccination. The immunogenicity and adverse reactions between ChAdOx1 nCov-19/AZD1222 and mRNA-1273 were compared. Results: Of the 243 rheumatic disease patients who received COVID-19 vaccines, 113 and 130 were immunized with AZD1222 and mRNA-1273, respectively. The anti-SARS-CoV-2 IgG seropositivity rate was 78.8% (89/113) for AZD1222 and 83.1% (108/130) for mRNA-1273. The level of anti-SARS-Cov-2 IgG was higher in patients who received mRNA-1273 than in those who received AZD1222. Prednisolone-equivalent dose >5 mg/day, methotrexate (MTX), non-anti-tumor necrosis factor (TNF)-a biologics, and Janus kinase (JAK) inhibitor use were associated with inferior immunogenicity. All reported adverse reactions were minor. More localized pain at the injection site and less fever and chills were observed in patients receiving mRNA-1273 compared with those receiving AZD1222. Rheumatic disease activities after vaccination remained stable in most patients. Conclusions: mRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity and adverse reaction profiles. Our study findings support temporary discontinuation of daily prednisolone dose >5 mg, MTX, non-anti-TNF-a biologics, or JAK inhibitors after COVID-19 vaccination.

2022-05-19 | GSE203081 | GEO

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

Project description: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.

2021-04-30 | E-MTAB-10431 | biostudies-arrayexpress

Augmenting SARS-CoV-2 vaccine induced spike protein-specific CD4+ T cell responses through IL-1β and its receptors.

Project description:Immunity to SARS-CoV-2 infection provided by COVID-19 mRNA vaccines decline over time. Thus, there is a need for interventions to augment and sustain such immunity. To address this, we characterized S protein-specific CD4+ T cells in healthy individuals who received COVID-19 mRNA vaccines utilizing high-dimensional single cell RNA-seq and mass cytometry. S protein-specific CD4+ T cells highly expressed IL-1 receptor (R) 1 and its decoy receptor IL-1R2. IL-1b promoted IFN-g expression by S protein-stimulated CD4+ T cells, which was furthered by adding anti-IL-1R2-blocking antibodies, supporting the functional implications of IL-1R1 and IL-1R2. Following the 2nd dose of a COVID-19 mRNA vaccine, IL-1R1 expression increased while IL-1R2 expression decreased in S protein-specific CD4+ T cells. Our findings provide novel insight into augmenting COVID-19 mRNA vaccine-induced CD4+ T cell immunity by modulating IL-1β and its receptor system, which could foster a more effective and prolonged immune response.

2023-03-01 | GSE206134 | GEO

Intranasal delivery of NS1-deleted influenza virus vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response (Hamster Lung RNA-seq Data)

Project description:The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and “anatomical escape” characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. In this study, we investigated immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants. Intranasal delivery of dNS1-RBD induced innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrained the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (IL-6, IL-1B, and IFN-γ) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden. To investigate the immune response, pathological process caused by SARS-CoV-2 Beta variants infection in Golden Hamster lung. Golden hamsters were vaccinated with dNS1-RBD vaccine at day0 and day 14, and 2 months later the vccinated hamster were challenged with SARS-CoV-2 Beta varians together with control group hamster. Then the lung samples were collected at 0, 1, 3, 5 post infection to sequence for the RNA-seq data, then performed gene expression analysis using data obtained from RNA-seq.

2023-05-28 | GSE228112 | GEO

Intranasal delivery of NS1-deleted influenza virus vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response (Mouse Lung RNA-seq Data)

Project description:The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and “anatomical escape” characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. In this study, we investigated immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants. Intranasal delivery of dNS1-RBD induced innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrained the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (IL-6, IL-1B, and IFN-γ) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden. To investigate the immune response generated by dNS1-RBD vaccine in C57BL/6 mouse lung, we vaccinated C57BL/6 mice and collect the lung samples to sequence for the RNA-seq data, then performed gene expression analysis using data obtained from RNA-seq of 5 different time points before and after vaccinated with dNS1-RBD vaccine.

2023-05-28 | GSE227647 | GEO

mRNA vaccine efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after the challenge

Project description:mRNA-1273, an mRNA-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is efficacious in mouse and non-human primate models of mild COVID-19. Hamsters exhibit more severe clinical disease from SARS-CoV-2, making it an important model to evaluate vaccine efficacy. Here we show that mock-vaccine treated hamsters infected with SARS-CoV-2 show weight loss and pulmonary infection with pathological changes and increased activated interstitial macrophages and other immune cell types. Prime-boost administration of mRNA-1273 elicited dose-independent robust binding and neutralizing antibodies, ameliorated weight loss and suppressed virus replication in the upper and lower airways. Vaccination largely prevented pulmonary pathological changes, antiviral immune cell activation and changes in cell type composition although increases in some immune cell types and activation of regulatory pathways were found and coincided with an anamnestic antibody response. The results characterize unexpected pulmonary cellular responses to SARS-CoV-2 in vaccinated animals that were shared but greatly attenuated, when compared to mock-vaccinated animals. The efficacy of mRNA-1273 is demonstrated as a two-dose vaccination schedule in a model of severe COVID-19.

2021-12-01 | GSE163838 | GEO

Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

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

2022-02-01 | E-MTAB-10129 | biostudies-arrayexpress

Intranasal delivery of NS1-deleted influenza virus vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response (Hamster AMs ATAC-seq Data)

Project description:The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and “anatomical escape” characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. In this study, we investigated immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants. Intranasal delivery of dNS1-RBD induced innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrained the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (IL-6, IL-1B, and IFN-γ) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden. To investigate the trainned-immunity of alveolar macrophage generated by dNS1-RBD vaccine in Golden Hamster, we vaccinated Golden Hamster with dNS1-RBD/dNS1-Vector/PBS and collect the alveolar macrophage samples to sequence for the ATAC-seq data 2 months post vaccinated. Then performed the differential peak and igv track visualization with this dataset.

2023-05-28 | GSE228111 | GEO

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