A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

15Identifying transcriptional responses that are most consistently associated with 16 experimental coronavirus (CoV) infection can help illuminate human cellular signaling 17 pathways impacted by CoV infection. Here, we distilled over 3,000,000 data points from 18 publically archived CoV infection transcriptomic datasets into consensus regulatory 19 signatures, or consensomes, that rank genes based on their transcriptional 20 responsiveness to infection of human cells by MERS, SARS-CoV-1 and SARS-CoV-2 21 subtypes. We computed overlap between genes with elevated rankings in the CoV 22 consensomes against those from transcriptomic and ChIP-Seq consensomes for nearly 23 880 cellular signaling pathway nodes. Validating the CoV infection consensomes, we 24 identified robust overlap between their highly ranked genes and high confidence targets 25 of signaling pathway nodes with known roles in CoV infection. We then developed a 26 series of use cases that illustrate the utility of the CoV consensomes for hypothesis 27 generation around mechanistic aspects of the cellular response to CoV infection. We 28 make the CoV infection consensomes and their universe of underlying data points freely 29 accessible through the Signaling Pathways Project web knowledgebase. 30 31 65 points in a series of use cases illuminates previously uncharacterized intersections 66 between CoV infection and human cellular signaling pathways. The CoV infection 67 consensome and its underlying datasets provide researchers with a unique and freely 68 accessible framework within which to generate and pressure test hypotheses around 69 human cellular signaling pathways impacted by CoV infection.70 71 72 73 5 Results 74Generation of the CoV consensomes 75 We first set out to generate a set of consensomes ranking human genes based on the 76 frequency of their significant differential expression in response to infection by MERS, 77 SARS1 and SARS2 CoVs. To do this we searched the Gene Expression Omnibus 78 (GEO) and ArrayExpress databases to identify datasets involving infection of human 79 cells by these species. From this initial collection of datasets, we next carried out a 80 three step quality control check as previously described (Ochsner et al., 2019), yielding 81 a total of 3,041,047 million data points in 111 experiments from 25 independent CoV 82 infection transcriptomic datasets (Supplementary information, Section 1). Using these 83 curated datasets, we next generated consensomes for each CoV species, as well as 84 one ranking genes across all CoV infection experiments (ALL CoV). As a reference 85 consensome for a virus whose transcriptional impact on human cells has been studied 86 in depth, we also generated a consensome for human influenza A virus (IAV) infection. 87The Supplementary information files contain the full human ALL CoV (Section 2), MERS 88 (Section 3), SARS1 (Section 4), SARS2 (Section 5) and IAV (Section 6) infection 89 transcriptomic consensomes. To assist researchers in inferring transcriptional regulation 90 of sig...

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“…ACE2 is repressed in pulmonary cells -a finding corroborated by other studies 56,57 -but inducible in gastrointestinal cells (Fig. 5).…”

supporting

confidence: 88%

Consensus transcriptional regulatory networks of coronavirus-infected human cells

Ochsner

Pillich

McKenna

2020

Preprint

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“…Regulatory elements in the ACE2 gene control the transcription of PIR (pirin), a negative regulator of NF-κB subunit RELA (p65). SARS-CoV-2 disruption of ACE2 is proposed to reduce PIR expression ( Fadason et al., 2020 ). PIR is proposed to function as a reversible switch that enables NF-κB response to changes in redox levels (oxidative stress) in the cell nucleus ( Liu et al., 2013 ).…”

Section: Cytokine Storm Featuring High Expression Of Il-6 and Tnf-αmentioning

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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“…The Genotype-Tissue Expression (GTEx) database revealed that SNP rs6629110 was associated with greater expression of ACE2 [ 5 ], although researchers were not able to confirm the link between variants in the ACE2 gene and COVID-19 [ 10 ]. The SNP rs2106806 was among those included in a recent study aimed at describing a transcription regulatory network within the ACE2 locus in the context of SARS-CoV-2 infection, but no correlation was found [ 11 ]. Here, we show that the minor A allele within rs2106806 increases the risk of critical COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Role of ACE2 genetic polymorphisms in susceptibility to SARS-CoV-2 among highly exposed but non infected healthcare workers

Martínez-Sanz

Jiménez

Martínez-Campelo

et al. 2021

Emerging Microbes & Infections

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We aim to evaluate the role of single-nucleotide polymorphisms of the angiotensin-converting enzyme 2 in susceptibility to SARS-CoV-2 infection. We included 28 uninfected but highly exposed healthcare workers and 39 hospitalized patients with COVID-19. Thirty-five SNPs were rationally selected. Two variants were associated with increased risk of being susceptible to SARS-CoV-2: the minor A allele in the rs2106806 variant (OR 3.75 [95% CI 1.23-11.43]) and the minor T allele in the rs6629110 variant (OR 3.39 [95% CI 1.09-10.56]). Evaluating the role of genetic variants in susceptibility to SARS-CoV-2 infection could help identify more vulnerable individuals and suggest potential drug targets for COVID-19 patients.

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A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

Cited by 12 publications

References 58 publications

Consensus transcriptional regulatory networks of coronavirus-infected human cells

Consensus transcriptional regulatory networks of coronavirus-infected human cells

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

Role of ACE2 genetic polymorphisms in susceptibility to SARS-CoV-2 among highly exposed but non infected healthcare workers

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