Multi-omics uncovers the immune landscape and molecular signatures associated with antibody-dependent cellular cytotoxicity in SARS-CoV-2 clearance
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE300023 | GEO | 2026/06/21
REPOSITORIES: GEO
Similar Datasets
Project description:The paper describes a model of ADCC.
Created by COPASI 4.26 (Build 213)
This model is described in the article:
A mathematical model of antibody-dependent cellular cytotoxicity (ADCC)
F. Hoffman, D. Gavaghan, J. Osborne, I.P. Barrett, T. You, H. Ghadially, R. Sainson, R.W. Wilkinson, H.M. Byrne
Journal of Theoretical Biology 436 (2018) 39–50
Abstract:
Immunotherapies exploit the immune system to target and kill cancer cells, while sparing healthy tis- sue. Antibody therapies, an important class of immunotherapies, involve the binding to specific antigens on the surface of the tumour cells of antibodies that activate natural killer (NK) cells to kill the tu- mour cells. Preclinical assessment of molecules that may cause antibody-dependent cellular cytotoxicity (ADCC) involves co-culturing cancer cells, NK cells and antibody in vitro for several hours and measuring subsequent levels of tumour cell lysis. Here we develop a mathematical model of such an in vitro ADCC assay, formulated as a system of time-dependent ordinary differential equations and in which NK cells kill cancer cells at a rate which depends on the amount of antibody bound to each cancer cell. Numerical simulations generated using experimentally-based parameter estimates reveal that the system evolves on two timescales: a fast timescale on which antibodies bind to receptors on the surface of the tumour cells, and NK cells form complexes with the cancer cells, and a longer time-scale on which the NK cells kill the cancer cells. We construct approximate model solutions on each timescale, and show that they are in good agreement with numerical simulations of the full system. Our results show how the processes involved in ADCC change as the initial concentration of antibody and NK-cancer cell ratio are varied. We use these results to explain what information about the tumour cell kill rate can be extracted from the cytotoxicity assays.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models .
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide.
Please refer to CC0 Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000802 | BioModels
Project description:The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n=6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan–β-CoV vaccines.
2024-12-31 | GSE283190 | GEO
Project description:NK cells are an essential component for the control of influenza infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of the NK cell CD16-receptor by antibody-coated influenza-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Though NK cell-mediated ADCC is an important mechanism to control influenza, influenza infection itself may act to enhance the potency of NK cell ADCC. To understand if virus-infected cells increase NK cell activation, we co-cultured human PBMCs with influenza-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate ADCC. Pre-incubation of PBMCs with influenza-infected target cells markedly enhanced the functionality of NK cells by ADCC antibodies in response to HA immune-complexes containing intravenous immunoglobulin (IVIG), allogenic target cells, with and without rituximab. Trans-well and supernatant transfer experiments showed that virus released into the supernatant is responsible for the enhanced functionality of NK cells, which is apparent at both the protein and RNA transcriptomic levels. Furthermore, cytokine multiplex data, RNA sequencing and cytokine blocking/supplementation experiments showed Type I interferons released from PBMCs were the primary mechanism of the influenza-induced increased NK cell functionality and ADCC potency. Importantly, the influenza infection-mediated increase in NK cell mediated anti-influenza ADCC was mimicked by the type I interferon agonist Poly-IC. This suggests a potential mechanism for enhancing monoclonal antibody therapies for influenza. We conclude that influenza-infection induced secretion of type I interferons enhances the ADCC capacity of NK cells and this pathway may potentially be manipulated to improve anti-influenza therapies.
2019-01-03 | GSE115203 | GEO
Project description:The COVID-19 pandemic prompted an unprecedented effort to develop effective countermeasures against SARS-CoV-2. While efficacious vaccines and certain therapeutic monoclonal antibodies are available, here, we report the development, cryo-EM structures and functional analyses of distinct potent monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 and its variant B.1.351. We established a platform for rapid identification of highly potent and specific SARS-CoV-2-neutralizing antibodies by high-throughput B cell receptor single cell sequencing of spike receptor binding domain immunized animals. We identified two highly potent and specific SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity. We also generated a bispecific antibody of these two lead clones. The lead monospecific and bispecific antibodies showed strong neutralization ability against prototypical SARS-CoV-2 and the highly contagious South African variant B.1.351 that post a further risk of reducing the efficacy of currently available therapeutic antibodies and vaccines. The lead mAbs showed potent in vivo efficacy against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We solved five cryo-EM structures at ~3 resolution of these neutralizing antibodies in complex with the ectodomain of the prefusion spike trimer, and revealed the molecular epitopes, binding patterns and conformations between the antibodies and spike RBD, which are distinct from existing antibodies. Our recently developed antibodies expand the repertoire of the toolbox of COVID-19 countermeasures against the SARS-CoV-2 pathogen and its emerging variants.
2022-01-11 | GSE174635 | GEO
Project description:<p>The COVID-19 pandemic has incurred tremendous costs worldwide and is still threatening public health in the 'new normal'. The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood. In the present work, we conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO) and healthy subjects. As a result, we identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients. Following feature selection, we built machine-learning-based classification models using 17 features (6 cytokines and 11 metabolites). Overall accuracies of more than 90% were attained in at least 6 machine-learning models. Of note, the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group. Furthermore, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2-specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination. Our findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indicate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.</p>
2024-08-26 | MTBLS3305 | MetaboLights
Project description:As the SARS-CoV-2 pandemic progressed, many monoclonal antibodies (mAbs) that neutralized infection against initial strains lost potency against later variants due to accumulation of mutations in the spike protein. Nonetheless, some mAbs, including S309, the parent of the therapeutically used sotrovimab, remained protective in animals against Omicron variants despite reduced neutralizing potential, with Fc-mediated effector functions likely sustaining inhibitory activity. Here, we identify Fc variants of S309 that confer enhanced protection against SARS-CoV-2 infection in a humanized Fcg receptor transgenic (Hu-FcgR Tg) mouse model of infection. Versions of S309 that are afucosylated (AFUC) and contain a G236A (GA) mutation in the Fc region showed increased binding to FcgRs IIA, IIIA, and IIIB and enhanced phagocytic activity in cell culture-based assays. Treatment with S309-GA-AFUC resulted in less viral burden, inflammation, and pulmonary ventilatory dysfunction in the lungs of Hu-FcgR Tg mice challenged with SARS-CoV-2 strains compared to the parental S309 mAb or a variant (S309-GRLR) lacking Fc effector functions. The enhanced protection in the lung conferred by S309-GA-AFUC required trafficking of CCR2-expressing monocytes to reduce SARS-CoV-2 viral burden and lung injury. Flow cytometry and RNA sequencing analyses showed that compared to the parental S309 mAb, S309-GA-AFUC treatment reduced the inflammatory state and induced a reparative transcriptional signature in monocytes and interstitial macrophages. Overall, our findings demonstrate that Fc engineering to increase antibody binding to activating FcgRs can strengthen effector functions, shape myeloid transcriptional profiles, and enhance protection against SARS-CoV-2 infection in vivo.
2025-12-15 | GSE313869 | GEO
Project description:Germinal centers (GC) are key sites for antibody diversification and affinity maturation. SARS-CoV-2 mRNA vaccines elicit robust GC B cell responses in humans, but how these influence the breadth of immunity against viral variants remains unclear. We analyzed GC B cell responses in nine healthy adults following mRNA booster immunization. We show that 77.8% of the B cell clones in the GC expressed representative monoclonal antibodies (mAbs) recognizing the spike protein, with 37.8% of these targeting the receptor-binding domain (RBD). One RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent XEC variant. mAb-52 utilized the IGHV3-66 public clonotype, protected hamsters challenged against the EG.5.1 variant, and targeted the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Its broad reactivity was driven by extensive somatic hypermutation, underscoring the critical role of GC reactions in shaping cross-variant B cell immunity following SARS-CoV-2 booster vaccination.
2025-09-16 | GSE292810 | GEO
Project description:The pandemic caused by SARS-CoV-2 is responsible for terrible health devastation with profoundly harmful consequences for the economic, social and political activities of communities on a global scale. Extraordinary efforts have been made by the world scientific community, who, in solidarity, shared knowledge so that effective vaccines could be produced quickly. However, it is still important to study therapies that can reduce the risk, until group immunity is reached, which, globally, will take a time that is still difficult to predict. On the other hand, the immunity time guaranteed by already approved vaccines is still uncertain.
The current study proposes a therapy whose foundation lies in the important role that innate immunity may have, by preventing the disease from progressing to the acute phase that may eventually lead to the patient’s death. Our focus is on NK cells and their relevant role.
Natural killer cells (NK) are considered the primary defense lymphocytes against virus-infected cells. They play a critical role in modulating the immune system. Preliminary studies in COVID-19 patients with severe disease, suggest a reduction in the number and function of NK cells, resulting in decreased clearance of infected and activated cells and unchecked elevation of inflammation markers that damage tissue. SARS-CoV-2 infection distorts the immune response towards a highly inflammatory phenotype. Restoring the effector functions of NK cells has the potential to correct the delicate immune balance needed to effectively overcome SARS-CoV-2 infection.
2022-06-22 | MODEL2202230002 | BioModels
Project description:Background: Type I interferons (IFNs) are essential to the clearance of viral diseases, in part by initiating upregulation of IFN regulated genes (IRGs). A clear distinction between genes upregulated directly by virus and genes upregulated by secondary IFN production has not been made. Here we investigated the genes regulated by IFN-a2b compared to the genes regulated by SARS-CoV infection in ferrets. Methods: We characterized early host immune responses in peripheral blood and lung necropsies of ferrets injected with IFN-a2b or infected with SARS-CoV/Tor 2 strain, using microarray analysis on the Affymetrix platform. Results: We identified a common IRG signature that was upregulated in both SARS-CoV infected ferrets as well as in ferrets injected with IFN-a2b. We also identified unique patterns of gene expression for leukocyte activation, cell adhesion and complement pathways between IFN-a2b injection and SARS-CoV infection. Conclusions: Our results define the effects of IFN-a2b on the immune system of ferrets highlighting genes regulated by IFN during SARS-CoV infection. We have shown the similarities and differences of top funcional gene groups as well as pathways that play key roles in early immune responses in ferrets in response to IFN-a2b or SARS-CoV. Key words: ferret, gene expression, SARS, interferon. Keywords: time course In experiments with IFN-a2b, for peripheral blood, 15 ferrets were randomly allocated to 3 groups: Day 0, 5 ferrets (no IFN injection), day 1, 6 ferrets (injected), and day 2, 4 ferrets (injected). For lung necropsies of injected ferrets with IFN-a2b, we used 12 ferrets in 3 groups: 4 ferrets, day 0 (no IFN injection), 4 ferrets, day 1 (injected) and 4 ferrets, day 2 (injected). Experimental groups for SARS-CoV infection was as follows: For peripheral blood, 3 and 4 ferrets for day 0 (no infection) and day 2 (infection) respectively. For lung neceropsies, a total of 9 ferrets in 3 groups, each with 3 replicates for day 0 (no infection), day 1 (infection) and day 2 (infection).
2010-12-01 | E-GEOD-22581 | biostudies-arrayexpress
Project description:Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. Methods: We examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. Results: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15RA further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2, and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. Conclusions: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.
2018-12-11 | GSE121682 | GEO