An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner

Kucia, Magdalena; Ratajczak, Janina; Bujko, Kamila; Adamiak, Mateusz; Ciechanowicz, Andrzej; Chumak, Vira; Brzeźniakiewicz‐Janus, Katarzyna; Ratajczak, Mariusz Z.

doi:10.1038/s41375-021-01332-z

Cited by 72 publications

(67 citation statements)

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“…SARS-CoV-2 Spike protein interacted with Toll-like receptor 4 (TLR4) and activated TLR4-mediated host innate immunity, 53 and a TLR4 receptor inhibitor TAK-242 significantly inhibited the Spike-induced cell pyroptosis. 54 Because NLRP3 inhibitor MCC950 treatment or NLRP3 knockdown did not affect live SARS-CoV-2-induced macrophage cell death determined by LDH release ( Figure. 1 E and Fig.…”

Section: Discussionmentioning

confidence: 95%

Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice

et al. 2022

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Background The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflammasome is activated upon SARS-CoV-2 infection and associated with COVID-19 severity. However, the processes by which the NLRP3 inflammasome is involved in COVID-19 disease remain unclear. Methods We infected THP-1 derived macrophages, NLRP3 knockout mice, and human ACE2 transgenic mice with live SARS-CoV-2 in Biosafety Level 3 (BSL-3) laboratory. We performed quantitative real-time PCR for targeted viral or host genes from SARS-CoV-2 infected mouse tissues, conducted histological or immunofluorescence analysis in SARS-CoV-2 infected mouse tissues. We also injected intranasally AAV-hACE2 or intraperitoneally NLRP3 inflammasome inhibitor MCC950 before SARS-CoV-2 infection in mice as indicated. Findings We have provided multiple lines of evidence that the NLRP3 inflammasome plays an important role in the host immune response to SARS-CoV-2 invasion of the lungs. Inhibition of the NLRP3 inflammasome attenuated the release of COVID-19 related pro-inflammatory cytokines in cell cultures and mice. The severe pathology induced by SARS-CoV-2 in lung tissues was reduced in Nlrp3 −/− mice compared to wild-type C57BL/6 mice. Finally, specific inhibition of the NLRP3 inflammasome by MCC950 alleviated excessive lung inflammation and thus COVID-19 like pathology in human ACE2 transgenic mice. Interpretation Inflammatory activation induced by SARS-CoV-2 is an important stimulator of COVID-19 related immunopathology. Targeting the NLRP3 inflammasome is a promising immune intervention against severe COVID-19 disease. Funding This work was supported by grants from the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to Y.G.Y.), the key project of the CAS “Light of West China” Program (to D.Y.) and Yunnan Province (202001AS070023 to D.Y.).

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Section: Discussionmentioning

confidence: 95%

Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice

et al. 2022

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“…Additionally, in terms of individual genes in the turquoise module, we identified hub-high traffic genes such as UTP14A ( 398 ), RUVBL2 ( 139 ), PRKCD ( 280 , 399 ), KEAP1 ( 400 – 402 ), CEBPA (TF) ( 403 ), RPL26L1 ( 404 ), PTPN6 ( 255 ), PPARA (TF) ( 405 ), TNFRSF1A ( 406 – 408 ), IKBKB ( 275 , 409 ), TFEB (TF) ( 410 , 411 ), PSMD4 ( 412 ), and ARHGAP1 ( 413 ), important components in immunopathogenesis of SARS-CoV-2. For example, the TNF receptor superfamily member 1A ( TNFRSF1A ) hub-high traffic gene may be a biomarker of mortality in severe COVID-19 patients, as increased expression of this gene was significantly correlated with mortalities ( 414 ).…”

Section: Discussionmentioning

confidence: 99%

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

et al. 2021

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BackgroundThe recent emergence of COVID-19, rapid worldwide spread, and incomplete knowledge of molecular mechanisms underlying SARS-CoV-2 infection have limited development of therapeutic strategies. Our objective was to systematically investigate molecular regulatory mechanisms of COVID-19, using a combination of high throughput RNA-sequencing-based transcriptomics and systems biology approaches.MethodsRNA-Seq data from peripheral blood mononuclear cells (PBMCs) of healthy persons, mild and severe 17 COVID-19 patients were analyzed to generate a gene expression matrix. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules in healthy samples as a reference set. For differential co-expression network analysis, module preservation and module-trait relationships approaches were used to identify key modules. Then, protein-protein interaction (PPI) networks, based on co-expressed hub genes, were constructed to identify hub genes/TFs with the highest information transfer (hub-high traffic genes) within candidate modules.ResultsBased on differential co-expression network analysis, connectivity patterns and network density, 72% (15 of 21) of modules identified in healthy samples were altered by SARS-CoV-2 infection. Therefore, SARS-CoV-2 caused systemic perturbations in host biological gene networks. In functional enrichment analysis, among 15 non-preserved modules and two significant highly-correlated modules (identified by MTRs), 9 modules were directly related to the host immune response and COVID-19 immunopathogenesis. Intriguingly, systemic investigation of SARS-CoV-2 infection identified signaling pathways and key genes/proteins associated with COVID-19’s main hallmarks, e.g., cytokine storm, respiratory distress syndrome (ARDS), acute lung injury (ALI), lymphopenia, coagulation disorders, thrombosis, and pregnancy complications, as well as comorbidities associated with COVID-19, e.g., asthma, diabetic complications, cardiovascular diseases (CVDs), liver disorders and acute kidney injury (AKI). Topological analysis with betweenness centrality (BC) identified 290 hub-high traffic genes, central in both co-expression and PPI networks. We also identified several transcriptional regulatory factors, including NFKB1, HIF1A, AHR, and TP53, with important immunoregulatory roles in SARS-CoV-2 infection. Moreover, several hub-high traffic genes, including IL6, IL1B, IL10, TNF, SOCS1, SOCS3, ICAM1, PTEN, RHOA, GDI2, SUMO1, CASP1, IRAK3, HSPA5, ADRB2, PRF1, GZMB, OASL, CCL5, HSP90AA1, HSPD1, IFNG, MAPK1, RAB5A, and TNFRSF1A had the highest rates of information transfer in 9 candidate modules and central roles in COVID-19 immunopathogenesis.ConclusionThis study provides comprehensive information on molecular mechanisms of SARS-CoV-2-host interactions and identifies several hub-high traffic genes as promising therapeutic targets for the COVID-19 pandemic.

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“…Nlrp3 inflammasome activation releases IL-1β, which is also an important stimulator for the expression of several proinflammatory cytokines, including TNF, IL-6, and IL-1α. This stimulation explains why activation of Nlrp3 inflammasomes in response to COVID19 infection leads to a cytokine storm and damage to HSPCs [ 79 – 81 ]. Nevertheless, the intriguing question remains whether activation of Nlrp3 inflammasomes within the hormetic zone promotes steady-state proliferation and post-transplantation expansion of HSPCs.…”

Section: Introductionmentioning

confidence: 99%

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

Ratajczak

Kucia

2021

Leukemia

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Hematopoietic and immune cells originate from a common hematopoietic/lymphopoietic stem cell what explains that these different cell types often share the same receptors and respond to similar factors. Moreover, the common goal of both lineages is to ensure tissue homeostasis under steady-state conditions, fight invading pathogens, and promote tissue repair. We will highlight accumulating evidence that innate and adaptive immunity modulate several aspects of hematopoiesis within the hormetic zone in which the biological response to low exposure to potential stressors generally is favorable and benefits hematopoietic stem/progenitor cells (HSPCs). Innate immunity impact on hematopoiesis is pleiotropic and involves both the cellular arm, comprised of innate immunity cells, and the soluble arm, whose major component is the complement cascade (ComC). In addition, several mediators released by innate immunity cells, including inflammatory cytokines and small antimicrobial cationic peptides, affect hematopoiesis. There are intriguing observations that HSPCs and immune cells share several cell-surface pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and cytosol-expressed NOD, NOD-like, and RIG-I-like receptors and thus can be considered “pathogen sensors”. In addition, not only lymphocytes but also HSPCs express functional intracellular complement proteins, defined as complosome which poses challenging questions for further investigation of the intracellular ComC-mediated intracrine regulation of hematopoiesis.

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An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner

Cited by 72 publications

References 15 publications

Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice

Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

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