SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.

Keywords: ACE2; COVID-19; RAGE; estrogen.

FIGURE 1

Network map of correlative expression of ERs (estrogen receptors) and related signaling genes (GPER1, ESR1, and ESR2) with RAGE, also associated to TMPRSS2 (A) and ACE2 (B) expression. Adapted from https://string‐db.org/ ,

FIGURE 2

Expression of RAGE in different tissues, mostly expressed in AT2 (alveolar type 2 pneumocyte) cells in lung. A, Values and correlations of RAGE gene expression in many organs, mostly in the lung (dark arrow). Adapted from https://gtexportal.org/., B, Data set Genes collected from integrated single‐cell RNA‐Seq analysis of patients with pulmonary fibrosis. RAGE (C3) detectable expression is far more pronounced in AT2 cells compared to other important proteins in SARS‐CoV‐2 infection process, such as ACE2 (C1) and TMPRSS2 (C2). Adapted from https://www.nupulmonary.org/

FIGURE 3

Comparison of potential glycosylation sites in amino acid sequence (A) of the spike protein of SARS‐CoV‐2 (GenBank QIC53213.1) and SARS‐CoV (GenBank AAU04646.1) vs hemagglutinin Influenza A (GenBank BAA01280.1), shows similar numbers of N, O, C glycosylation in coronavirus and fewer glycosylation points in H1N1, as illustrated in histograms of N‐glycosylation sites (B). Adapted from www.cbs.dtu.dk/services/NetNGlyc (Gupta, Jung and Brunak. In preparation, 2004) www.cbs.dtu.dk/services/NetCGlyc ; www.cbs.dtu.dk/services/NetOGlyc. C, The crystallography structure of spike protein SARS‐CoV‐2 and hemagglutinin of Influenza A extracted from Protein Data Bank (https://www.rcsb.org; PDB ID: 6VXX, PDB ID: 6HJR1 ¹⁵² ) shows dark arrows pointing carbohydrate sites, which are more frequent in SARS‐CoV‐2

FIGURE 4

Integrated signaling pathway and summary of events promoted by SARS‐CoV‐2 infection in human cells. This scheme describes the cellular response to SARS‐CoV‐2 entry into the cell mediated by ACE2, which can be modulated by estrogen signaling via transcriptional pathway. Under a pro‐inflammatory response, RAGE can be stimulated by AGE, PAMP, S100A, or HMGB1, which activates NADPH and PLC (phospholipase C). NADPH elevates intracellular ROS levels, which may act in the PI3K‐AKT or AGT (angiotensin) pathway. The PLC activates the PKC, which activates the signaling pathways of ERK 1/2, JNK, and PI3K‐AKT. This results in activation of NF‐κB and ERK 1/2 that ends in AP1 and gene transcription. Regarding renin‐angiotensin signaling, AGT and AngA (angiotensin A) stimulate ATR1, leading to the activation of PI3K‐AKT signaling pathway, promoting eNOS release. In turn, ATR1 also activates the SRC (proto‐oncogene non‐receptor tyrosine kinase), which activates Shc‐Ras and finally MEK‐ERK 1/2, heading to gene transcription. The estrogen pathway can also interfere with the internalization of SARS‐CoV‐2, due to its modulation of ACE2 gene transcription via Raf‐MEK‐ERK 1/2 pathway, which can be mediated by nuclear membrane receptors or associated with G protein. Adapted from KEGG (Kyoto Encyclopedia of Genes and Genomes) and Xiang et al Therefore, according to literature data, here, we propose that estrogen receptors activation may participate in modulation of ACE2 levels and modulation of RAGE cell response, which in turn could reduce inflammation in COVID‐19