Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV

Abstract

The 2019-nCoV is reported to share the same entry (ACE2) as SARS-CoV according to the updated findings. Analyzing the distribution and expression level of the route of coronavirus may help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different, suggesting relatively similar susceptibility. Besides, based on the expression of ACE2 in smoking individuals, we inferred that long-term smoking might be a risk factor for 2019-nCoV. Analyzing the ACE2 in SARS-CoV infected cells suggested that ACE2 was more than just a receptor but also participated in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we also constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may explain the clinical symptoms so far and help clinicians and researchers understand the pathogenesis and design therapeutic strategies for 2019-nCoV. : medRxiv preprint GO biological process annotation gmt file was downloaded from MSigDB (https://www.gsea-msigdb.org/gsea/msigdb/). GSEA was performed to analyze the possible biological processes related to ACE2 in healthy people using clusterProfiler (12). The parameters were nPerm = 1000, minGSSize = 10, maxGSSize = 500, the biological processes with p-value < 0.05 were considered significant. GSVA was performed using GSVA R package. The immune infiltrating was quantified using the ssGSEA method in GSVA R package. The gene list for immune cells was derived from Bindea G et al.(13). PPIAll viral-related biological process and cytokine secretion-biological process proteins were extracted from the gmt file, Cytoscape v3.7.2 was used to construct the PPI network using BisoGenet application, the PPI sources include DIP, BIOGRID, HPRD, INTACT, MINT and BIND. And the nodes with topological importance in the interaction network were screened by calculating Degree Centrality (DC) with the Cytoscape plugin CytoNCA. Hub proteins were identified using Cytoscape plugin CytoHubba.

COVID‐19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019‐nCoV disease

“…inflammatory cytokine storm (Chen, Liu, et al, 2020;Zumla et al, 2020); a life-threatening condition characterized by elevated levels of interleukin 6 (IL-6) in plasma. A number of investigations recently conducted on COVID-19 have reported that IL-6 levels was actually higher in the patients with severe disease (Cai, 2020;Chen, Liu, et al, 2020;Xiang et al, 2020). This could highlight the importance of IL-6 as a biomarker for evaluation of disease severity (Chen, Zhao, et al, 2020).…”

Clinical features of acute kidney injury in Coronavirus disease 2019—A case report with review of literature

“…The development of AKI is an important negative prognostic indicator for survival with SARS [8].Another human coronavirus, MERS-CoV, was reported to enter target cells via by binding to dipeptidyl-peptidase 4 (DPP-4), which is one of the major brush border membrane proteins in the kidney and is also present in glomerular podocytes and capillaries, during an outbreak in 2012 [9].A previous report showed that more than one-fourth of MERS-CoV-infected patients developed AKI [10].SARS-CoV-2 was shown to be more likely to use ACE2 as the entry receptor, which is previously known as the receptor for SARS-CoV [11]. However,ACE2 was demonstrated to be more than just a receptor during SARS-CoV-2 infection, as it is also involved in post-infection regulation, including immune response, cytokine secretion, and genome replication [3]. This high degree of similarity in the cellular mechanism of SARS-CoV-2 and SARS-CoV suggests that the risk factors of kidney injury may be similar.…”

“…Both bioinformatics modeling and in vitro experiments have indicated that SARS-CoV-2 is more likely to enter target cells via the receptor angiotensin-converting-enzyme 2 (ACE2), which is a cellular mechanism identical to the SARS-CoV [3].A previous report showed that the level of ACE2 expressed in urinary organs was much higher than that in respiratory organs, and ACE2 in the kidney was disturbed within the renal tubular epithelium, vascular smooth muscle cells of the intrarenal arteries, and the glomeruli [4,5]. This suggests that the kidney is a possible target infected by SARS-CoV-2.…”

Yin-Yang Balance of ACE/ACE2 Pathways: The Rational for ACE2 Pathway Inhibitor Administration in SARS-CoV-2 Patients

“…Moreover, a compound that mimics the angiotensin (Ang)-(1-7) actions has been shown to induce IL-10 upregulation via a Mas receptor-dependent pathway in bronchoalveolar lavage 15 . Of note, IL-10 is one of the cytokines downstream ACE2 pathway 6 and together with IL-6 is significantly upregulated in the most severe (SARS) cases 2 , suggesting an important correlation between ACE2/Ang (1-7) axis activation and SARS.…”

“…Indeed, there is evidence that soluble forms of ACE2 are active and even associated to pathological conditions 5 . Moreover, a recent integrative bioinformatics analysis shows that the expression of ACE2 in human bronchial cells infected with SARS-CoV is dramatically increased 24h after infection and remained at a high level for at least 2 days, suggesting that ACE2 may be involved in a positive feed-back loop post-infection 6 . In the same report, it has been shown that expression level of ACE2 in bronchial epithelium obtained by brushing from asthmatic and normal subjects was similar, suggesting that respiratory epithelial cells of healthy subjects and asthmatic patients have similar ability to bind to SARS-CoV-2 through ACE2.…”