Murine studies and expressional analyses of human cardiac pericytes reveal novel trajectories of SARS-CoV-2 Spike protein-induced microvascular damage

Avolio, Elisa; Srivastava, Prashant K.; Ji, Jiahui; Carrabba, Michele; Tsang, Christopher T. W.; Gu, Yan; Thomas, Anita C.; Gupta, Kapil; Berger, Imre; Emanueli, Costanza; Madeddu, Paolo

doi:10.1038/s41392-023-01489-2

Cited by 2 publications

(2 citation statements)

References 11 publications

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“…An increase abundance score for pericytes was also identified in infected lungs at 5 dpi (but not other times) (S4 Fig). Pericytes express ACE2 and binding of spike protein has been shown in vitro to induce profound transcriptional changes in these cells [81, 82], which may explain this result.…”

Section: Resultsmentioning

confidence: 99%

“…Lower frequencies of ILC2 cells have been associated with severe COVID-19 [85]. An increase abundance score for pericytes was also identified in infected lungs at 5 dpi (but not other times) (S4b Fig) . Pericytes express ACE2 and binding of spike protein has been shown in vitro to induce profound transcriptional changes in these cells [86,87], which may explain this result. At 10 dpi, in addition to nuocytes, significantly increased abundance of three more cell types associated with repair and return to homeostasis was evident (Fig.…”

Section: Ba1 Induced Histopathological Lesions In Lungs That Resolved...mentioning

confidence: 99%

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Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

Carolin,

Yan,

Bishop

et al. 2024

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied, less well understood are the inflammatory signatures in lung tissues associated with mild disease or silent infections, wherein infection and inflammation are rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq and histological analyses of lungs over time in an omicron BA.1/K18-hACE2 mouse infection model, which displays these latter features. Although robust infection was evident at 2 days post infection (dpi), viral RNA was largely cleared by 10 dpi. Acute inflammatory signatures showed a slightly different pattern of cytokine signatures compared with severe infection models, but where much diminished 30 dpi and absent by 66 dpi. Cellular deconvolution identified significantly increased abundance scores for a number of anti-inflammatory pro-resolution cell types at 5/10 dpi. These included type II innate lymphoid cells, T regulatory cells, and interstitial macrophages. Genes whose expression trended downwards over 2 - 66 dpi included biomarkers of severe disease and were associated with 'cytokine storm' pathways. Genes whose expression trended upward during this period were associated with recovery of ciliated cells, AT2 to AT1 transition, reticular fibroblasts and innate lymphoid cells, indicating a return to homeostasis. Very few differentially expressed host genes were identified at 66 dpi, suggesting near complete recovery. The parallels between mild or subclinical infections in humans and those observed in this BA.1/K18-hACE2 mouse model are discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Ba1 Induced Histopathological Lesions In Lungs That Resolved...mentioning

confidence: 99%

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

Carolin,

Yan,

Bishop

et al. 2024

Preprint

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Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling

Van Tin,

Rethi,

Higa

et al. 2024

Cells

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Background: The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to viral entry and can cause cardiac injuries. Toll-like receptor 4 (TLR4) and NOD-, LPR-, and pyrin-domain-containing 3 (NLRP3) inflammasome are critical immune system components implicated in cardiac fibrosis. The spike proteins activate NLRP3 inflammasome through TLR4 or angiotensin-converting enzyme 2 (ACE2) receptors, damaging various organs. However, the role of spike proteins in cardiac fibrosis in humans and the interactions of spike proteins with NLRP3 inflammasomes and TLR4 remain poorly understood. Methods: We utilized scratch assays, Western blotting, and immunofluorescence to evaluate the migration, fibrosis signaling, mitochondrial calcium levels, reactive oxygen species (ROS) production, and cell morphology of cultured human cardiac fibroblasts (CFs) treated with spike (S1) proteins for 24 h with or without an anti-ACE2 neutralizing antibody, a TLR4 blocker, or an NLRP3 inhibitor. Results: S1 protein enhanced CFs migration and the expressions of collagen 1, α-smooth muscle actin, transforming growth factor β1 (TGF-β1), phosphorylated SMAD2/3, interleukin 1β (IL-1β), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). S1 increased ROS production but did not affect mitochondrial calcium content and cell morphology. Treatment with an anti-ACE2 neutralizing antibody attenuated the effects of S1 on collagen 1 and TGF-β1 expressions. Moreover, NLRP3 (MCC950) and NF-kB inhibitors, but not the TLR4 inhibitor TAK-242, prevented the S1-enhanced CFs migration and overexpression of collagen 1, TGF-β1, and IL-1β. Conclusion: S1 activates human CFs by priming NLRP3 inflammasomes through NF-κB signaling in an ACE2-dependent manner.

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Murine studies and expressional analyses of human cardiac pericytes reveal novel trajectories of SARS-CoV-2 Spike protein-induced microvascular damage

Cited by 2 publications

References 11 publications

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling

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