The Glycan Ectodomain of SARS-CoV-2 Spike Protein Modulates Cytokine Production and Expression of CD206 Mannose Receptor in PBMC Cultures of Pre-COVID-19 Healthy Subjects

• Published in: Viruses Vol. 16; no. 4; p. 497
• Main Authors: Barbati, Cristiana, Bromuro, Carla, Vendetti, Silvia, Torosantucci, Antonella, Cauda, Roberto, Cassone, Antonio, Palma, Carla
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.03.2024; MDPI
• Subjects: Antigens; CD3 antigen; Cell activation; Cells, Cultured; Concanavalin A; Concanavalin A - metabolism; COVID-19; COVID-19 - immunology; COVID-19 - metabolism; COVID-19 - virology; COVID-19 infection; COVID-19 vaccines; Cytokines; Cytokines - metabolism; Glycoproteins; Health aspects; Healthy Volunteers; HU protein; Humans; IFN-γ; IL-6; Immunity; Immunological memory; Immunomodulation; Inflammation; insects; Interferon-gamma - metabolism; Interleukin 6; Interleukin-6 - metabolism; Lectins; Lectins, C-Type - metabolism; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lymphocyte Activation; Lymphocytes T; Macrophages; Mannan; Mannose; Mannose Receptor; Mannose-Binding Lectins - metabolism; memory; Memory cells; mitogens; Monosaccharides; N-glycans; Pandemics; PBMC; Peripheral blood mononuclear cells; Polysaccharides; Polysaccharides - metabolism; Properties; protein sources; Proteins; Receptors, Cell Surface - metabolism; SARS-CoV-2 - immunology; SARS-CoV-2 - metabolism; SARS-CoV-2 spike proteins; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Sugars; T cell mitogen; T cells; T-lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Yeast; yeasts; γ-Interferon; Italy; United States > US; SARS-CoV-2 spike proteins; immunomodulation; IFN-γ; T cell mitogen; PBMC; mannose receptor (CD206); IL-6
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v16040497

The ability of recombinant, SARS-CoV-2 Spike (S) protein to modulate the production of two COVID-19 relevant, pro-inflammatory cytokines (IL-6 and IFN-γ) in PBMC cultures of healthy, pre-COVID-19 subjects was investigated. We observed that cytokine production was largely and diversely modulated by the S protein depending on antigen or mitogen stimulation, as well as on the protein source, insect (S-in) or human (S-hu) cells. While both proteins co-stimulated cytokine production by polyclonally CD3-activated T cells, PBMC activation by the mitogenic lectin Concanavalin A (Con A) was up-modulated by S-hu protein and down-modulated by S-in protein. These modulatory effects were likely mediated by the S glycans, as demonstrated by direct Con A-S binding experiments and use of yeast mannan as Con A binder. While being ineffective in modulating memory antigenic T cell responses, the S proteins and mannan were able to induce IL-6 production in unstimulated PBMC cultures and upregulate the expression of the mannose receptor (CD206), a marker of anti-inflammatory M2 macrophage. Our data point to a relevant role of N-glycans, particularly N-mannosidic chains, decorating the S protein in the immunomodulatory effects here reported. These novel biological activities of the S glycan ectodomain may add to the comprehension of COVID-19 pathology and immunity to SARS-CoV-2.