Pyroptosis of syncytia formed by fusion of SARS-CoV-2 spike and ACE2-expressing cells

Ma, Huabin; Zhu, Zhoujie; Lin, Hongzhi; Wang, Shanshan; Zhang, Peipei; Li, Yanguo; Li, Long; Wang, Jinling; Zhao, Yufen; Han, Jiahuai

doi:10.1038/s41421-021-00310-0

Cited by 45 publications

(38 citation statements)

References 18 publications

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“… 31 , 61 Thus, the chromatin-cGAS-IFN signaling axis needs to be tightly regulated to prevent immunopathological outcomes, especially at late disease stages. Moreover, syncytial cells can undergo lytic cell death such as pyroptosis, 22 , 62 which results in the release of damage-associated molecular patterns (DAMPs) such as nucleic acids and ATP. 63 These DAMPs could be recognized by neighboring cells, triggering the production of proinflammatory cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

Zhou

Zhang

Lei

et al. 2021

Sig Transduct Target Ther

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The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

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Section: Discussionmentioning

confidence: 99%

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

Zhou

Zhang

Lei

et al. 2021

Sig Transduct Target Ther

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“…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]. These results suggested that syncytia might be an important player for the immune dysregulation and pathogenesis of patients with COVID-19.…”

Section: Introductionmentioning

confidence: 97%

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.

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“…For the β-coronavirus infection, cells were reported to undergo PANoptosis, which consisted of pyroptosis, apoptosis, and necroptosis [21,22]. Previous studies have shown that SARS-CoV-2 can induce these three kinds of programed cell death in susceptible epithelial cells and immune cells [23][24][25]. As for ferroptosis, whose morphological and biochemical features are distinct from PANoptosis, new castle virus (NDV) was the first virus to be discovered as a ferroptosis inducer in tumor cells [26].…”

Section: Introductionmentioning

confidence: 99%

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Xia

Zhang

You

2021

Viruses

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Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.

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Pyroptosis of syncytia formed by fusion of SARS-CoV-2 spike and ACE2-expressing cells

Cited by 45 publications

References 18 publications

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

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

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

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