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The Receptor Binding Domain of SARS-CoV-2 Omicron Subvariants Targets Siglec-9 to Decrease the Immunogenicity by Preventing Phagocytosis of Macrophages

ABSTRACT: The Receptor Binding Domain of SARS-CoV-2 Omicron Subvariants Targets Siglec-9 to Decrease the Immunogenicity by Preventing Phagocytosis of Macrophages

PROVIDER: PRJNA1056269 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27334137_1.fastq.gz	Fastqsanger.gz
	SRR27334137_2.fastq.gz	Fastqsanger.gz
	SRR27334138_1.fastq.gz	Fastqsanger.gz
	SRR27334138_2.fastq.gz	Fastqsanger.gz
	SRR27334139_1.fastq.gz	Fastqsanger.gz

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The Receptor Binding Domain of SARS-CoV-2 Omicron Subvariants Targets Siglec-9 to Decrease the Immunogenicity by Preventing Phagocytosis of Macrophages

Project description:SARS-CoV-2 Omicron infection results in a milder clinical feature compared to the Delta strain. The development of Omicron specific vaccine has also been hampered due to the low immunogenicity. By reverse-mutating the amino acids in the Omicron receptor binding domain (RBD), we identified that the mutation from Phenylalanine 375 (F375) in the Omicron spike to Serine 375 (S375) in Delta and other early strains significantly enhances the immune response in the manner of vaccines. Interestingly, the new evolution of the 371FAPF375FAF sequence in Omicron exhibited a potent inhibitory effect on macrophage uptake of the RBD nanoparticle or spike-pseudovirus particles. Omicron RBD enhances binding to Siglec-9 on macrophages to reduce the immunogenicity and increase the immune evasion, which could be abrogated by Serine 375 mutation. Based upon these observations, we further developed a bivalent Omicron RBD with S375 mutation and Delta RBD nanoparticle vaccine, which elicited potent and broad neutralizing antibodies in mice, rabbits, and rhesus macaques. Our research suggests that manipulating the Siglec-9 pathway could be a promising approach to enhancing vaccine response. Importantly, our findings suggest that Omicron subvariants have developed a new strategy to evade immune surveillance by impairing the phagocytosis and antigen presentation processes of macrophages.

2023-12-28 | GSE251973 | GEO

Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-Î± in vitro and that Siglec-H ko mice produce more IFN-Î± after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed

2016-03-16 | E-GEOD-79248 | biostudies-arrayexpress

Immunological and Metabolic Characteristics of the Omicron Variants Infection

Project description:The Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wild-type SARS-CoV-2. Omicron could not be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescent individuals who were infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8+ T cell epitopes, compared with Delta. These epitopes could induce robust CD8+ T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8+ T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted memory T cell responses. Consistently, a higher fraction of memory CD8+ T cells were found in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.

2023-03-11 | PXD037955 | Pride

Effect of soluble Siglec-14 on macrophage polarization

Project description:Influence of soluble Siglec-14 on macrophage poloarization was examined by analyzing the transcripts from human macrophages cultured in the presence or absence of recombinant soluble Siglec-14 protein

2018-10-29 | GSE121311 | GEO

Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.

2016-03-16 | GSE79248 | GEO

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Project description:We used mRNA-seq analysis to explore the transcriptional response induced in BV-2 cells by stable overexpression Siglec-F and related human Siglec receptors compared to loss-of-function 2xY->F mutant receptors.

2020-09-01 | GSE149153 | GEO

Siglec-3 (CD33) and Siglec-8 ligands

Project description:Identification of human brain ligand for the microglial inhibitory receptors Siglec-3 (CD33) and Siglec-8

2022-03-07 | PXD032064 | JPOST Repository

Prior vaccination exceeds prior infection in eliciting innate and humoral immune responses in Omicron infected outpatients

Project description:Antibody response following Omicron infection is reported to be less robust than that to other variants. Here we investigated how prior vaccination and/or prior infection modulates that response. Disease severity, antibody responses and immune transcriptomes were characterized in four groups of Omicron-infected outpatients (n=83): unvaccinated/no prior infection, vaccinated/no prior infection, unvaccinated/prior infection and vaccinated/prior infection. The percentage of patients with asymptomatic or mild disease was highest in the vaccinated/no prior infection group (87%) and lowest in the unvaccinated/no prior infection group (47%). Significant anti-Omicron spike antibody levels and neutralizing activity were detected in the vaccinated group immediately after infection but were not present in the unvaccinated/no prior infection group. Within two weeks, antibody levels against Omicron, increased. Omicron neutralizing activity in the vaccinated group exceeded that of the prior infection group. No increase in neutralizing activity in the unvaccinated/no prior infection group was seen. The unvaccinated/prior infection group showed an intermediate response. We then investigated the early transcriptomic response following Omicron infection in these outpatient populations and compared it to that found in unvaccinated hospitalized patients with Alpha infection. Omicron infected patients showed a gradient of transcriptional response dependent upon whether or not they were previously vaccinated or infected. Vaccinated patients showed a significantly blunted interferon response as compared to both unvaccinated Omicron infected outpatients and unvaccinated Alpha infected hospitalized patients typified by the response of specific gene classes such as OAS and IFIT that control anti-viral responses and IFI27, a predictor of disease outcome.

2022-06-11 | GSE201530 | GEO

Siglec receptors modulate dendritic cell activation and antigen presentation to T cells in cancer

Project description:Sialoglycan - Siglec axis has been reported to modulate the functions of multiple immune cell types. We found that inhibitory molecules human Siglec-9 and mouse Siglec-E both expressed at high level in tumor-infiltrating dendritic cells(DCs). Therefore, we generated mouse DC cell line lacking the expression of Siglec-E, and used bulk RNA sequencying to analyse how Siglec-E affects DC functions.

2022-03-23 | GSE190700 | GEO

RNA sequencing to determine gene expression changes in Siglec-15 knockdown oteosarcoma cells

Project description:In our study, we found that Siglec-15 was critical to osteosarcoma characteristics. To identify the downstream target genes of Siglec-15 in osteosarcoma, we conducted the RNA-seq analysis of Siglec-15 knockdown in osteosarcoma cell line 143B cells.

2021-05-25 | GSE175414 | GEO

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