SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination

Zhang, Zhengrong; You, Zheng; Niu, Zubiao; Zhang, Bo; Wang, Chenxi; Yao, Xiaohong; Peng, Haoran; Franca, del Nonno; Wang, Yunyun; Zhu, Yichao; Su, Yan; Tang, Meng; Jiang, Xiaoyi; Ren, He; He, Mingbo; Wang, Yuqi; Gao, Lihua; Zhao, Ping; Shi, Hanping; Chen, Zhaolie; Wang, Xiaoning; Piacentini, Mauro; Bian, Xiu‐Wu; Melino, Gerry; Liu, Liang; Huang, Hongyan; Sun, Qiang

doi:10.1038/s41418-021-00782-3

Cited by 131 publications

(172 citation statements)

References 48 publications

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“…The histology of 41 lung samples from COVID-19 patients show that 87% of them display dysmorphic pneumocytes with syncytia (Bussani et al, 2020). In vitro studies have also shown syncytia formation in hiPSC-derived neurons, hiPSC-derived astrocytes, U2OS-ACE2, Vero-ACE2, and 293T-ACE2 after viral infection (Buchrieser et al, 2020;Wang et al, 2021;Zhang et al, 2021). Recent papers propose that a unique bi-arginine motif within the S1/S2 cleavage site of SARS-CoV-2 spike glycoprotein mediates the fusion of neighboring ACE2 + cells and formation of syncytia (Braga et al, 2021;Zhang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have also shown syncytia formation in hiPSC-derived neurons, hiPSC-derived astrocytes, U2OS-ACE2, Vero-ACE2, and 293T-ACE2 after viral infection (Buchrieser et al, 2020;Wang et al, 2021;Zhang et al, 2021). Recent papers propose that a unique bi-arginine motif within the S1/S2 cleavage site of SARS-CoV-2 spike glycoprotein mediates the fusion of neighboring ACE2 + cells and formation of syncytia (Braga et al, 2021;Zhang et al, 2021). Furthermore, previous studies have found that syncytia mediated by SARS-CoV-2 as well as other viruses such as human immunodeficiency virus-1 (HIV-1) and reovirus-associated FAST proteins can lead to apoptosis (Scheller and Jassoy, 2001;Salsman et al, 2005;Nardacci et al, 2015;Buchrieser et al, 2020), This suggests that apoptosis in virus infected cultures becomes exacerbated via syncytia formation and cytopathy affects can be alleviated by targeting the relevant downstream processes specific to that cell type and virus.…”

Section: Discussionmentioning

confidence: 99%

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Deleterious Effects of SARS-CoV-2 Infection on Human Pancreatic Cells

Shaharuddin

Wang

Santos

et al. 2021

Front. Cell. Infect. Microbiol.

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COVID-19 pandemic has infected more than 154 million people worldwide and caused more than 3.2 million deaths. It is transmitted by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and affects the respiratory tract as well as extra-pulmonary systems, including the pancreas, that express the virus entry receptor, Angiotensin-Converting Enzyme 2 (ACE2) receptor. Importantly, the endocrine and exocrine pancreas, the latter composed of ductal and acinar cells, express high levels of ACE2, which correlates to impaired functionality characterized as acute pancreatitis observed in some cases presenting with COVID-19. Since acute pancreatitis is already one of the most frequent gastrointestinal causes of hospitalization in the U.S. and the majority of studies investigating the effects of SARS-CoV-2 on the pancreas are clinical and observational, we utilized human iPSC technology to investigate the potential deleterious effects of SARS-CoV-2 infection on iPSC-derived pancreatic cultures containing endocrine and exocrine cells. Interestingly, iPSC-derived pancreatic cultures allow SARS-CoV-2 entry and establish infection, thus perturbing their normal molecular and cellular phenotypes. The infection increased a key cytokine, CXCL12, known to be involved in inflammatory responses in the pancreas. Transcriptome analysis of infected pancreatic cultures confirmed that SARS-CoV-2 hijacks the ribosomal machinery in these cells. Notably, the SARS-CoV-2 infectivity of the pancreas was confirmed in post-mortem tissues from COVID-19 patients, which showed co-localization of SARS-CoV-2 in pancreatic endocrine and exocrine cells and increased the expression of some pancreatic ductal stress response genes. Thus, we demonstrate that SARS-CoV-2 can directly infect human iPSC-derived pancreatic cells with strong supporting evidence of presence of the virus in post-mortem pancreatic tissue of confirmed COVID-19 human cases. This novel model of iPSC-derived pancreatic cultures will open new avenues for the comprehension of the SARS-CoV-2 infection and potentially establish a platform for endocrine and exocrine pancreas-specific antiviral drug screening.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Deleterious Effects of SARS-CoV-2 Infection on Human Pancreatic Cells

Shaharuddin

Wang

Santos

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Therefore, CIC structures are also regarded as a way for tissues to maintain homeostasis (29,30). Disorder in this process may lead to tumors or diseases such as immune-related disorders (8,(31)(32)(33). At present, literatures have reported CIC structures in tumor tissues, including urothelial carcinoma (34), buccal mucosa squamous cell carcinoma (10), pancreatic ductal adenocarcinoma (9), metastatic adenocarcinoma (34), head and neck squamous cell carcinoma (35), renal cell carcinoma (36), gastric cancer (37), breast carcinoma (11,38), small cell carcinoma of lung (39), benign tendon sheath giant cell carcinoma specimen (40), malignant mesothelioma (41), leiomyolipoma (42), etc., but there is no study on the CIC structures in the tissues of esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, CIC formation as a mechanism of cell cannibalism that is induced by the establishment of epithelial adhesion could inhibit transformed growth, suggesting that CIC structuremediated cell killing might also be a potential tumor suppressive pathway (7,20). Cannibalistic behavior, as one of the mechanisms involving CIC formation, may increase nutrient intake by feeding upon other cells, and escape from the specific immune response by engulfing lymphocytes (33). In this scenario, upregulation of phagocytosis in human tumor cells may be similar to that of some unicellular microorganisms, of which the goal is to survive and propagate in a hostile microenvironment (8,45).…”

Section: Discussionmentioning

confidence: 99%

Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

et al. 2021

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Cell-in-cell (CIC) structures are defined as the special structures with one or more cells enclosed inside another one. Increasing data indicated that CIC structures were functional surrogates of complicated cell behaviors and prognosis predictor in heterogeneous cancers. However, the CIC structure profiling and its prognostic value have not been reported in human esophageal squamous cell Carcinoma (ESCC). We conducted the analysis of subtyped CIC-based profiling in ESCC using “epithelium-macrophage-leukocyte” (EML) multiplex staining and examined the prognostic value of CIC structure profiling through Kaplan-Meier plotting and Cox regression model. Totally, five CIC structure subtypes were identified in ESCC tissue and the majority of them was homotypic CIC (hoCIC) with tumor cells inside tumor cells (TiT). By univariate and multivariate analyses, TiT was shown to be an independent prognostic factor for resectable ESCC, and patients with higher density of TiT tended to have longer post-operational survival time. Furthermore, in subpopulation analysis stratified by TNM stage, high TiT density was associated with longer overall survival (OS) in patients of TNM stages III and IV as compared with patients with low TiT density (mean OS: 51 vs 15 months, P = 0.04) and T3 stage (mean OS: 57 vs 17 months, P=0.024). Together, we reported the first CIC structure profiling in ESCC and explored the prognostic value of subtyped CIC structures, which supported the notion that functional pathology with CIC structure profiling is an emerging prognostic factor for human cancers, such as ESCC.

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“…However, the mechanism by which the SARS-CoV-2 S protein regulates the formation of these syncytia is not fully clear. A study has found that SARS-CoV-2 S protein mediated lymphocyte elimination through syncytia (7). Infected cells form syncytia through membrane fusion with minimal S protein, making be challenging to obtain neutralizing antibodies and prevent them through antibodies effectively (8).…”

Section: Introductionmentioning

confidence: 99%

COVID-19: The CaMKII_Like System of S Protein Drives Membrane Fusion and Induces Syncytial Multinucleated Giant Cells

Liu

Li²

2021

Preprint

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COVID-19 is a unique disease characterized by extensive pulmonary thrombosis and infected syncytial multinucleated giant cells, relating to extensive tissue damage. The SARS-CoV-2 S protein on the membrane of infected cells can initiate receptor-dependent syncytia formation. To study the membrane fusion on S protein, we adopted structural domain search methods to analyze the structural and non-structural proteins of the SARS-COV-2 virus in this study. The results showed that the surface glycoprotein (S) had conserved domains of CaMKII: CaMKII_AD, CaATP_NAI, DUF4440, EF-hand, Protein kinase, and SnoaL-like. Comparing to SARS-COV and MERS, only the CaATP_NAI of SARS-COV-2 is in the contact position of the viral membrane and cell membrane. We believed that when the EF-hand domain (“YEQYIKWPWYIWLGF”) of S protein bound to calcium ions, S2 protein had CaMKII protein activities. After the S protein fusion peptide was inserted into the infected cell membrane and fixed the S2 protein on the cell membrane, the CaMKII_AD prompted the S2 protein to form HR1-HR2 six-helix bundles. The HR1-HR2 hexamer had three CaATP_NAI domains (“APAICHDGKAHFPRE”) near the viral membrane (contact position), the CaATPase activated by magnesium ions, and released energy through ATP phosphorylation. The CaATPase drove the HR1-HR2 hexamer fold irreversibly toward the viral membrane. Then the CaATP_NAI and CaMKII_AD domains extended to the outside and combined the viral membrane and the cell membrane so that the contact position formed a thin barrel structure. The hydrated calcium ions are gathered in the barrel structure to create a calcium bridge. The release action of water in contact position caused the instability of the double membrane, triggering lipid mixing and fusion of the membrane. CaATPases disassembled the barrel structure, and HR1-HR2 hexamer is fell into the cytoplasm. The viral membrane fused with the cell membrane on a large scale. The cytoplasmic contents of the virus mixed with the cell. The S protein of the infected cell may bind to the ACE2 receptor of another cell (or also an infected cell) and then achieved membrane fusion through a similar principle, forming cell syncytia, includes syncytial multinucleated giant cells. The membrane fusion could disrupt the calcium homeostasis in human body, and increased the risk of coagulation and vascular calcification.

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SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination

Cited by 131 publications

References 48 publications

Deleterious Effects of SARS-CoV-2 Infection on Human Pancreatic Cells

Deleterious Effects of SARS-CoV-2 Infection on Human Pancreatic Cells

Subtype-Based Analysis of Cell-in-Cell Structures in Esophageal Squamous Cell Carcinoma

COVID-19: The CaMKII_Like System of S Protein Drives Membrane Fusion and Induces Syncytial Multinucleated Giant Cells

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