Negative regulation of<i>ACE2</i>by interferons<i>in vivo</i>and its genetic control

Ansari, Azim; Marchi, Emanuele; Ramamurthy, Narayan; Aschenbrenner, Dominik; Hackstein, Carl-Philipp; S-K., Lin; Bowden, Rory; Sharma, Eshita; Pedergnana, Vincent; Venkateswaran, Suresh; Kugathasan, Subra; Mo, Angela; Gibson, Greg; McLauchlan, John; Barnes, Eleanor; Baillie, J Kenneth; Teichmann, Sarah A.; Mentzer, Alexander J.; Todd, John; Knight, Julian C.; Uhlig, Holm H.; Klenerman, Paul

doi:10.1101/2020.04.26.20080408

Cited by 6 publications

(6 citation statements)

References 56 publications

(93 reference statements)

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“…Although the mouse and human ACE2 and TMPRSS2 expression data align nearly perfectly in the olfactory epithelium (Brann et al, 2020), there may be clinically relevant divergences between species in the olfactory bulb and brain (Hodge et al, 2019;Maresh et al, 2008). Finally, it is important to note that the ACE2 gene is regulated by inflammation in human cells, and other SARS-CoV-2 entry genes may be similarly modulated by primary infection and inflammation (Ansari et al, 2020;Ziegler et al, 2020). This observation raises the possibility that a broader spectrum of cells expresses ACE2 during SARS-CoV-2 infection than is currently appreciated.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

Cooper

Brann

Farruggia

et al. 2020

Neuron

299

365

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The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.

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Section: Discussionmentioning

confidence: 99%

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

Cooper

Brann

Farruggia

et al. 2020

Neuron

299

365

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“…It is known that many cell types respond to IFN-I with varying transcriptional responses [ 25 ]. Thus, the ability of IFN-I to increase the expression of different ISGs including ACE2 can vary widely depending on the different cell type composition of the respiratory sample analyzed [ 13 , 14 ]. Furthermore, our data confirmed that flACE2 did not increase after IFNβ treatment [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we hypothesized that CF patients might exhibit a differential expression of ACE2, furin and TMPRSS2 in the upper respiratory tract cells, which might impact on the SARS-CoV-2 infection and/or spread. Moreover, as there are contrasting results on the relationship between IFN-I and ACE2 isoforms expression [ 13 , 14 ], we aimed to study the relationship of ACE2 (all isoforms), furin and TMPRSS2 with IFN stimulated gene 15 (ISG15), a well-established ISG that acts as a potential modifier of CF severity, as well as ACE2 responsiveness to ex vivo IFN-I stimulation [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Entry Genes Expression in Relation with Interferon Response in Cystic Fibrosis Patients

et al. 2021

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The expression rate of SARS-CoV-2 entry genes, angiotensin-converting enzyme 2 (ACE2), the main viral receptor and the proteases, furin and transmembrane serine protease 2 (TMPRSS2) in cystic fibrosis (CF) individuals is poorly known. Hence, we examined their levels in upper respiratory samples of CF patients (n = 46) and healthy controls (n = 45). Moreover, we sought to understand the interplay of type I interferon (IFN-I) with ACE2, furin and TMPRSS2 by evaluating their gene expression with respect to ISG15, a well-known marker of IFN activation, in upper respiratory samples and after ex vivo IFNβ exposure. Lower ACE2 levels and trends toward the reduction of furin and TMPRSS2 were found in CF patients compared with the healthy controls; decreased ACE2 amounts were also detected in CF individuals with pancreatic insufficiency and in those receiving inhaled antibiotics. Moreover, there was a strong positive correlation between ISG15 and ACE2 levels. However, after ex vivo IFNβ stimulation of nasopharyngeal cells, the truncated isoform (dACE2), recently demonstrated as the IFN stimulated one with respect to the full-length isoform (flACE2), slightly augmented in cells from CF patients whereas in those from healthy donors, dACE2 levels showed variable levels of upregulation. An altered expression of SARS-COV-2 entry genes and a poor responsiveness of dACE2 to IFN-I stimulation might be crucial in the diffusion of SARS-CoV-2 infection in CF.

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“…In the presence of RNA virus infection, ACE2 expression shows a significant negative correlation with IFN pathway genes. One of these SNPs is located near a frameshift mutation that disables the production of IFN-l4 (Ansari et al, 2020). As both ACE2 and receptors for IFN-l are preferentially expressed on type II alveolar pneumocytes, their association may be relevant in COVID-19 pathology, as suppressed IFN-l expression coupled with elevated ACE2 expression could simultaneously suppress epithelial defense while amplifying the viral load.…”

Section: Weak Interferon Defense and Neutrophil-driven Cytotoxicity Imentioning

confidence: 99%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-l-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcgRIIA) and downstream signaling pathways (e.g., NF-kB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-a/ IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers,

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Negative regulation ofACE2by interferonsin vivoand its genetic control

Cited by 6 publications

References 56 publications

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

SARS-CoV-2 Entry Genes Expression in Relation with Interferon Response in Cystic Fibrosis Patients

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

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