ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modelling revealed how Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

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ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

eLife ◽

10.7554/elife.74623 ◽

2022 ◽

Vol 11 ◽

Author(s):

Riem Gawish ◽

Philipp Starkl ◽

Lisabeth Pimenov ◽

Anastasiya Hladik ◽

Karin Lakovits ◽

...

Keyword(s):

Mouse Model ◽

Adaptive Immunity ◽

Proinflammatory Cytokines ◽

In Silico ◽

Immune Cell ◽

Inhalation Therapy ◽

Immune Cell Infiltration ◽

Efficient Treatment ◽

Critical Aspects

In silico modelling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNg and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

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Selective In Vivo Visualization of Immune-Cell Infiltration in a Mouse Model of Autoimmune Myocarditis by Fluorine-19 Cardiac Magnetic Resonance

Circulation Cardiovascular Imaging ◽

10.1161/circimaging.112.000125 ◽

2013 ◽

Vol 6 (2) ◽

pp. 277-284 ◽

Cited By ~ 42

Author(s):

Ruud B. van Heeswijk ◽

Jonathan De Blois ◽

Gabriela Kania ◽

Christine Gonzales ◽

Przemyslaw Blyszczuk ◽

...

Keyword(s):

Cardiac Magnetic Resonance ◽

Magnetic Resonance ◽

Mouse Model ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Autoimmune Myocarditis

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Indigo Pulverata Levis (Chung-Dae, Persicaria tinctoria) Alleviates Atopic Dermatitis-like Inflammatory Responses In Vivo and In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms23010553 ◽

2022 ◽

Vol 23 (1) ◽

pp. 553

Author(s):

Ga-Yul Min ◽

Ji-Hye Kim ◽

Tae-In Kim ◽

Won-Kyung Cho ◽

Ju-Hye Yang ◽

...

Keyword(s):

Atopic Dermatitis ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Hacat Cells ◽

Serum Ige ◽

Tnf Α ◽

Inflammatory Chemokines

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with a type 2 T helper cell (Th2) immune response. The IndigoPulverata Levis extract (CHD) is used in traditional Southeast Asian medicine; however, its beneficial effects on AD remain uninvestigated. Therefore, we investigated the therapeutic effects of CHD in 2,4-dinitrochlorobenzene (DNCB)-induced BALB/c mice and tumor necrosis factor (TNF)-α- and interferon gamma (IFN)-γ-stimulated HaCaT cells. We evaluated immune cell infiltration, skin thickness, and the serum IgE and TNF-α levels in DNCB-induced AD mice. Moreover, we measured the expression levels of pro-inflammatory cytokines, mitogen-activated protein kinase (MAPK), and the nuclear factor-kappa B (NF-κB) in the mice dorsal skin. We also studied the effect of CHD on the translocation of NF-κB p65 and inflammatory chemokines in HaCaT cells. Our in vivo results revealed that CHD reduced the dermis and epidermis thicknesses and inhibited immune cell infiltration. Furthermore, it suppressed the proinflammatory cytokine expression and MAPK and NF-κB phosphorylations in the skin tissue and decreased serum IgE and TNF-α levels. In vitro results indicated that CHD downregulated inflammatory chemokines and blocked NF-κB p65 translocation. Thus, we deduced that CHD is a potential drug candidate for AD treatment.

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SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

10.1101/2021.12.10.472112 ◽

2021 ◽

Author(s):

Scott B Biering ◽

Francielle Tramontini Gomes de Sousa ◽

Laurentia V. Tjang ◽

Felix Pahmeier ◽

Richard Ruan ◽

...

Keyword(s):

Transcriptional Response ◽

Barrier Dysfunction ◽

Vascular Leak ◽

Endothelial Barrier Dysfunction ◽

Mechanistic Insight ◽

Starting Point ◽

Signaling Axis ◽

Insight Into

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.

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Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus-Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration in a Mouse Model

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.02.986 ◽

2017 ◽

Vol 137 (9) ◽

pp. 1895-1904 ◽

Cited By ~ 15

Author(s):

Ji-Young Lim ◽

Da-Bin Ryu ◽

Sung-Eun Lee ◽

Gyeongsin Park ◽

Chang-Ki Min

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Graft Versus Host Disease ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Host Disease ◽

Graft Versus Host

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Drosophila immune cells extravasate from vessels to wounds using Tre1 GPCR and Rho signaling

The Journal of Cell Biology ◽

10.1083/jcb.201801013 ◽

2018 ◽

Vol 217 (9) ◽

pp. 3045-3056 ◽

Cited By ~ 5

Author(s):

Leila Thuma ◽

Deborah Carter ◽

Helen Weavers ◽

Paul Martin

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Innate Immune ◽

Murine Models ◽

Pupal Development ◽

Epithelial Migration ◽

Drosophila Model ◽

Rate Limiting ◽

Insight Into

Inflammation is pivotal to fight infection, clear debris, and orchestrate repair of injured tissues. Although Drosophila melanogaster have proven invaluable for studying extravascular recruitment of innate immune cells (hemocytes) to wounds, they have been somewhat neglected as viable models to investigate a key rate-limiting component of inflammation—that of immune cell extravasation across vessel walls—due to their open circulation. We have now identified a period during pupal development when wing hearts pulse hemolymph, including circulating hemocytes, through developing wing veins. Wounding near these vessels triggers local immune cell extravasation, enabling live imaging and correlative light-electron microscopy of these events in vivo. We show that RNAi knockdown of immune cell integrin blocks diapedesis, just as in vertebrates, and we uncover a novel role for Rho-like signaling through the GPCR Tre1, a gene previously implicated in the trans-epithelial migration of germ cells. We believe this new Drosophila model complements current murine models and provides new mechanistic insight into immune cell extravasation.

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Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

Nature Communications ◽

10.1038/s41467-019-12551-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Brianna J. Klein ◽

Suk Min Jang ◽

Catherine Lachance ◽

Wenyi Mi ◽

Jie Lyu ◽

...

Keyword(s):

Posttranslational Modification ◽

Memory Impairment ◽

Target Genes ◽

Epigenetic Mark ◽

Mechanistic Insight ◽

Genomic Analyses ◽

Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

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