Yi Zhu 
Publications
SARS-CoV-2 Spike protein promotes vWF secretion and thrombosis via endothelial cytoskeleton-associated protein 4 (CKAP4).
Li Kan K Yao Liu L Wang Jin J Song Hao H Zhang Yan-Hong YH Bai Xue X Zhang Kai K Zhou Dong-Ming DM Ai Ding D Zhu Yi Y
Signal transduction and targeted therapy 20220922 1
Similar Datasets
Project description:This experiment aims to profile polyclonal antibody binding profiles in serum from vaccinated animals relative to antibody function in a virus neutralization assay. Rabbits received three vaccinations with a DNA vaccine encoding the spike protein of the SARS-CoV-2 index strain. Serum samples were selected based on a three-tier (low, intermediate, and high) capacity to cross-neutralize SARS-CoV-2 strains with known neutralization resistance. Following normalization of total anti-spike IgG levels, serum of each animal (n=3) were evaluated for antibody binding to 10mer cyclic constrained peptides spanning the entire spike protein and regions with known SARS-CoV-2 variant of concern spike mutations.
2023-08-31 | E-MTAB-13040 | biostudies-arrayexpress
Project description:We here identified that the trimeric spike protein of SARS-CoV-2 could bind to TLR4 directly and robustly activate downstream signaling in monocytes and neutrophils. Moreover, specific TLR4 or NFKB inhibitor, or knockout of MyD88 could significantly block IL-1B induction by spike protein. We thus reveal that spike protein of SARS-CoV-2 functions as a potent stimulus causing TLR4 activation and sepsis related abnormal responses.
2021-02-25 | GSE167480 | GEO
Project description:The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details that underlie these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular and cellular pathways associated with SARS-CoV-2 pathogenesis, we performed transcriptomic analyses of bronchoalveolar lavage (BAL) samples and peripheral blood, and proteomics analyses of serum from infected rhesus macaques. We observed upregulation of macrophage signatures, complement cascade pathways, platelet activation, and markers of thrombosis in BAL and peripheral blood as well as extensive macrophage infiltrates in lung. These observations coincided with robust induction of interferon and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFa and NF-κB as well as downstream signaling pathways. These findings suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2 induced vascular disease. Our findings also suggest potential novel therapeutic targets for COVID-19 disease.
2020-10-20 | GSE156701 | GEO
Project description:Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single-dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Furthermore, we validated the protective efficacy of the Ad26.COV2.S against proinflammatory pathways and coagulation cascade in rhesus macaques by proteomics. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters.
2022-03-26 | GSE196893 | GEO
Project description:Human cardiac pericytes express the receptors for SARS-CoV-2 and contribute to microvascular dysfunction in COVID-19 patients. The SARS-CoV-2 capsid Spike protein seems to play a direct role in COVID-19 microangiopathy, but it is not known yet whether the Spike protein alone, without the infectious virus, can induce transcriptional alterations in pericytes. This study investigated the signalling pathways activated by the Spike protein in cultured human cardiac pericytes. We found that 309 RNA transcripts were significantly modulated in pericytes exposed to the Spike protein, with the upregulation of pathways linked to inflammation and viral infection.
2023-05-09 | GSE218644 | GEO
Project description:We evaluated virus-induced damages in perfused human blood vessels from iPS-derived vascular organoid (iVO). By taking advantage of the cranial window model, iVOs were transplanted to develop human blood vessels by anastomosing the recipient mouse circulatory system. we infused SARS-CoV-2 spike protein (extracellular domain, ECD) in the mouse to determine the impact on chimeric human-mouse blood vessels formed under the cranial window. Our iVO transplantation studies indicated that Spike protein could specifically target human endothelial cells, but not murine endothelial cells, which leads to neutrophil migration by creating a coagulopathic milieu and therein generating microthrombi.
2023-10-05 | GSE235232 | GEO
Project description:mRNA vaccination of individuals with prior SARS-CoV-2 infection provides superior protection against breakthrough infections with variants of concern compared to vaccination in the absence of prior infection. However, the immune mechanisms by which this ‘hybrid immunity’ is generated and maintained are unknown. While genetic variation in spike glycoprotein effectively subverts neutralizing antibodies, spike-specific T cells are generally maintained against SARS-CoV-2 variants. Thus, we comprehensively profiled T cell responses against the S1 and S2 domains of spike glycoprotein in a cohort of SARS-CoV-2-naive or convalescent individuals who received two-dose mRNA vaccine series and were matched by age, sex, and vaccine type. Using flow cytometry, we observed that the overall functional breadth of CD4 T cells as well as polyfunctional Th1 responses were similar between the two groups. However, polyfunctional cytotoxic CD4 T cell responses against both S1 and S2 domains trended higher among convalescent subjects. Multi-modal single-cell RNA sequencing revealed diverse functional programs in spike-specific CD4 and CD8 T cells in both groups. However, convalescent individuals displayed enhanced cytotoxic and antiviral CD8 T cell responses to both S1 and S2 in the absence of cytokine production. Taken together, our data suggest that cytotoxic CD4 and CD8 T cells targeting spike glycoprotein may partially account for hybrid immunity and protection against breakthrough infections with SARS-CoV-2.
2023-03-01 | GSE223236 | GEO
Project description:Intranasal vaccines can prime or recruit to the respiratory epithelium mucosal immune cells capable of preventing transmission of SARS-CoV-2. We found that a single intranasal dose of serotype 5-based adenoviral vectors expressing either the receptor binding domain (Ad5-RBD) or the complete ectodomain (Ad5-S) of the SARS-CoV-2 spike protein was effective in inducing i) secretory and serum anti-spike IgA and IgG, ii) robust SARS-CoV-2-neutralizing activity in the serum and in respiratory secretions, iii) rigorous spike-directed T helper 1 cell/cytotoxic T cell immunity, and iv) protection of wild-type mice from a challenge with the SARS-CoV-2 beta variant. Our data confirm and extend previous studies reporting promising preclinical results on vector-based intranasal SARS-CoV-2 vaccination, and support the potential of this approach to elicit mucosal immunity for preventing reinfection and transmission of SARS-CoV-2 more effectively than the currently available vaccines.
2023-05-01 | GSE223476 | GEO
Project description:Cytokine release syndrome (CRS) is one of the leading causes of mortality in COVID-19 patients caused by the SARS-CoV-2 coronavirus. However, the mechanism of CRS induced by SARS-CoV-2 is vague. This study shows that dendritic cells loaded with spike protein of SARS-CoV-2 stimulate T cells to release much more IL-2, which subsequently cooperates with spike protein to facilitate peripheral blood mononuclear cells to release IL-1β, IL-6, and IL-8. The aim of this sequencing is to find the key molecular of IL-2 synergistic spike protein releasing much more inflammatory factors in PBMCs and to explore the molecular mechanism.
2024-09-13 | GSE241843 | GEO
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