Syncytia formation during SARS-CoV-2 lung infection: a disastrous unity to eliminate lymphocytes

Lin, Lilong; Li, Qing; Wang, Ying; Shi, Yufang

doi:10.1038/s41418-021-00795-y

Cited by 84 publications

(85 citation statements)

References 16 publications

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“…SARS-CoV-2 infection could induce syncytia formation of infected cells [9], which was shown to be able to internalize lymphocytes to form cell-in-cell structures [10], a type of unique cellular structure usually prevalent in human tumor tissues [11][12][13]. The lymphocytes enclosed into the syncytia primarily underwent cell death, contributing to lymphopenia in patients with COVID-19 [14]. The syncytia themselves were recently shown to succumb to cell death by pyroptosis, potentially enhancing inflammation in the infected patients [15].…”

Section: Introductionmentioning

confidence: 99%

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

Ren

Peng

et al. 2021

Biol Direct

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SARS-CoV-2 infection could cause severe acute respiratory syndrome, largely attributed to dysregulated immune activation and extensive lung tissue damage. However, the underlying mechanisms are not fully understood. Here, we reported that viral infection could induce syncytia formation within cells expressing ACE2 and the SARS-CoV-2 spike protein, leading to the production of micronuclei with an average rate of about 4 per syncytium (> 93%). Remarkably, these micronuclei were manifested with a high level of activation of both DNA damage response and cGAS-STING signaling, as indicated by micronucleus translocation of γH2Ax and cGAS, and upregulation of their respective downstream target genes. Since activation of these signaling pathways were known to be associated with cellular catastrophe and aberrant immune activation, these findings help explain the pathological effects of SARS-CoV-2 infection at cellular and molecular levels, and provide novel potential targets for COVID-19 therapy.

show abstract

Section: Introductionmentioning

confidence: 99%

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

Ren

Peng

et al. 2021

Biol Direct

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“…Syncytia) can be induced by certain types of viral infections, such as HIV, respiratory syncytial virus, and HSV 41 . Syncytia formation has been reported in the literature associated with SARS-COV-2 infection [42][43][44] , most notably in histopathologic lung sections from patients who died from COVID-19 44 . Another relevant nding is that Vero E6 cells, upon expressing the SARS-CoV-2 spike protein, could form syncytia as long as the ACE2 is present, but they cannot when transfected with SARS-CoV spike protein 43 , implying that cell fusion capability may be speci c to SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 95%

“…Another relevant nding is that Vero E6 cells, upon expressing the SARS-CoV-2 spike protein, could form syncytia as long as the ACE2 is present, but they cannot when transfected with SARS-CoV spike protein 43 , implying that cell fusion capability may be speci c to SARS-CoV-2. It is reasonable to think that virus-induced cell fusion can facilitate the transfer of the viral genome to the neighboring cells 42 by sharing cytoplasm between the cells. We observed signi cant Syncytia events only in the SARS-CoV-2 infected Vero E6 cells and not in the uninfected cells.…”

Section: Discussionmentioning

confidence: 99%

“…In targeting TNT, the proven clinical e cacy in treating COVID19 of Colchicine, a microtubule inhibitor that might interfere with TNT formation 60,61 , can be suggestive evidence of the role of TNT in COVID19 pathogenesis. Drugs that suppress cell fusion have been tested in vitro 44 ; among them, niclosamide, an oral anti-helminthic agent, was effective in cell protection against virus-induced cell death 42,44 . Drugs that interfere with EV machinery at large have been tested even before the COVID-19 pandemic.…”

Section: Discussionmentioning

confidence: 99%

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An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy

Merolli

Kasaei

Ramsamy

et al. 2021

Preprint

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SARS-CoV-2 virions enter the host cells by docking their spike glycoproteins to the membrane-bound Angiotensin Converting Enzyme 2. After intracellular assembly, the newly formed virions are released from the infected cells to propagate the infection, using the extra-cytoplasmic ACE2 docking mechanism. However, the molecular events underpinning SARS-CoV-2 transmission between host cells are not fully understood. Here, we report the findings of a scanning Helium-ion microscopy study performed on Vero E6 cells infected with mNeonGreen-expressing SARS-CoV-2. Our data reveal, with unprecedented resolution, the presence of: 1)-long tunneling nanotubes that connect two or more host cells over submillimeter distances; 2)-large scale multiple cell fusion events (syncytia); and 3)-abundant extracellular vesicles of various sizes. Taken together, these ultrastructural features describe a novel intra-cytoplasmic connection among SARS-CoV-2 infected cells that may act as an alternative route of viral transmission, disengaged from the well-known extra-cytoplasmic ACE2 docking mechanism. Our findings may explain the elusiveness of SARS-CoV-2 to survive from the immune surveillance of the infected host.

show abstract

Section: Introductionmentioning

confidence: 99%

Micronucleus Production, Activation of DNA Damage Response and cGAS-STING Signaling in Syncytia Induced by SARS-CoV-2 Infection

Ren

Peng

et al. 2021

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 infection could cause severe acute respiratory syndrome, largely attributed to dysregulated immune activation and extensive lung tissue damage. However, the underlying mechanisms are not fully understood. Here, we reported that viral infection could induce syncytia formation within cells expressing ACE2 and the SARS-CoV-2 spike protein, leading to the production of micronuclei with an average rate of about 4 per syncytium (> 93%). Remarkably, these micronuclei were manifested with a high level of activation of both DNA damage response and cGAS -STING signaling, as indicated by micronucleus translocation of gH2Ax and cGAS, and upregulation of their respective downstream target genes. Since activation of these signaling pathways were known to be associated with cellular catastrophe and aberrant immune activation, these findings help explain the pathological effects of SARS-CoV-2 infection at cellular and molecular levels, and provide novel potential targets for COVID-19 therapy.

show abstract

Syncytia formation during SARS-CoV-2 lung infection: a disastrous unity to eliminate lymphocytes

Cited by 84 publications

References 16 publications

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection

An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy

Micronucleus Production, Activation of DNA Damage Response and cGAS-STING Signaling in Syncytia Induced by SARS-CoV-2 Infection

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