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The Secret Life of ACE2 as a Receptor for the Coronaviruses

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "SARS-CoV-2 and COVID-19".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 8469

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Special Issue Editor

Prof. Dr. Jianxun Qi

E-Mail Website
Guest Editor

Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Interests: viruses; envelop protein; receptor; ligand–receptor interaction; immunogen design

Special Issue Information

Dear Colleagues,

The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a huge threat to public health. To date, there have been >600,000,000 confirmed cases of COVID-19, including > 6 million deaths globally. After the characterization of SARS-CoV-2, its receptor was quickly determined to be the ACE2, which is also the receptor of other coronaviruses, such as SARS-CoV, the causative agent of SARS, NL63 that causes common cold-like disease, and SARS-CoV/SARS-CoV-2-related sarbecoviruses identified in animals. The trimeric S protein is the major glycoprotein on the coronaviruses’ envelope and responsible for engaging the receptor for viral entry, and thus, it is a prime target for vaccine design and therapeutic antibody development. The receptor-binding domain (RBD) in the S protein plays an essential role in ACE2 receptor recognition.

The Special Issue entitled “The Secret Life of ACE2 as a Receptor for the Coronaviruses” aims to present recent research on any aspect of the ACE2 receptor and S protein interaction. Some of its focal points include but are not limited to the following:

The binding properties and structural basis of coronavirus S/RBD to ACE2;
The expression profile of ACE2 and its relationship with the pathogenesis of coronaviruses;
Therapeutics against coronaviruses’ infection targeting ACE2;
The interspecies transmission of coronaviruses.

Reviews, original research, and communications will be welcome. We look forward to receiving your submissions for this Special Issue.

Prof. Dr. Jianxun Qi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

coronavirus
sarbecovirus
SARS-CoV-2
SARS-CoV
NL63
entry
pathogenesis
variants of concern
S protein
receptor-binding domain (RBD)
ACE2
expression profile
tropism
polymorphism
SNP
ligand–receptor interaction
therapeutics
antibodies
small molecules
peptide inhibitor

Published Papers (5 papers)

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Research

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17 pages, 3106 KiB

Open AccessArticle

MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake

by Quirin Emslander, Karsten Krey, Sabri Hamad, Susanne Maidl, Lila Oubraham, Joshua Hesse, Alexander Henrici, Katharina Austen, Julia Mergner, Vincent Grass and Andreas Pichlmair

Viruses 2023, 15(8), 1763; https://doi.org/10.3390/v15081763 - 18 Aug 2023

Cited by 1 | Viewed by 1253

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the central entry receptor for SARS-CoV-2. However, surprisingly little is known about the effects of host regulators on ACE2 localization, expression, and the associated influence on SARS-CoV-2 infection. Here we identify that ACE2 expression levels are regulated by the E3 ligase MDM2 and that MDM2 levels indirectly influence infection with SARS-CoV-2. Genetic depletion of MDM2 elevated ACE2 expression levels, which strongly promoted infection with all SARS-CoV-2 isolates tested. SARS-CoV-2 spike-pseudotyped viruses and the uptake of non-replication-competent virus-like particles showed that MDM2 affects the viral uptake process. MDM2 ubiquitinates Lysine 788 of ACE2 to induce proteasomal degradation, and degradation of this residue led to higher ACE2 expression levels and superior virus particle uptake. Our study illustrates that cellular regulators of ACE2 stability, such as MDM2, play an important role in defining the infection capabilities of SARS-CoV-2. Full article

(This article belongs to the Special Issue The Secret Life of ACE2 as a Receptor for the Coronaviruses)

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16 pages, 2575 KiB

Open AccessArticle

Tumor Necrosis Factor and Interleukin-1β Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation

by Michinori Ishitoku, Sho Mokuda, Kei Araki, Hirofumi Watanabe, Hiroki Kohno, Tomohiro Sugimoto, Yusuke Yoshida, Takemasa Sakaguchi, Junya Masumoto, Shintaro Hirata and Eiji Sugiyama

Viruses 2023, 15(7), 1498; https://doi.org/10.3390/v15071498 - 3 Jul 2023

Cited by 1 | Viewed by 1853

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) and the auxiliary receptor Neuropilin-1 (NRP1) to enter host cells. NRP1 has another isoform, NRP2, whose function in COVID-19 has seldom been reported. In addition, although patients with severe cases of COVID-19 often exhibit increased levels of proinflammatory cytokines, the relationship between these cytokines and SARS-CoV-2 proliferation remains unknown. The aim of this study is to clarify the roles of proinflammatory cytokines in Neuropilin expressions and in SARS-CoV-2 infection. To identify the expression patterns of NRP under inflamed and noninflamed conditions, next-generation sequencing (RNA-seq), immunohistochemistry, quantitative real-time PCR, and Western blotting were performed using primary cultured fibroblast-like synoviocytes, MH7A (immortalized cell line of human rheumatoid fibroblast-like synoviocytes), immortalized MRC5 (human embryonic lung fibroblast), and synovial tissues. To measure viral proliferative capacity, SARS-CoV-2 infection experiments were also performed. NRP2 was upregulated in inflamed tissues. Cytokine-stimulated human fibroblast cell lines, such as MH7A and immortalized MRC5, revealed that NRP2 expression increased with co-stimulation of tumor necrosis factor α (TNFα) and interleukin-1 beta (IL-1β) and was suppressed with anti-TNFα antibody alone. TNFα and IL-1β promoted SARS-CoV-2 proliferation and Spike protein binding. The viral proliferation coincided with the expression of NRP2, which was modulated through plasmid transfections. Our results revealed that proinflammatory cytokines, including TNFα, contribute to NRP2 upregulation and SARS-CoV-2 proliferation in host human cells. Full article

(This article belongs to the Special Issue The Secret Life of ACE2 as a Receptor for the Coronaviruses)

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14 pages, 6617 KiB

Open AccessArticle

Structural Basis for the Enhanced Infectivity and Immune Evasion of Omicron Subvariants

by Yaning Li, Yaping Shen, Yuanyuan Zhang and Renhong Yan

Viruses 2023, 15(6), 1398; https://doi.org/10.3390/v15061398 - 20 Jun 2023

Cited by 1 | Viewed by 1312

Abstract

The Omicron variants of SARS-CoV-2 have emerged as the dominant strains worldwide, causing the COVID-19 pandemic. Each Omicron subvariant contains at least 30 mutations on the spike protein (S protein) compared to the original wild-type (WT) strain. Here we report the cryo-EM structures of the trimeric S proteins from the BA.1, BA.2, BA.3, and BA.4/BA.5 subvariants, with BA.4 and BA.5 sharing the same S protein mutations, each in complex with the surface receptor ACE2. All three receptor-binding domains of the S protein from BA.2 and BA.4/BA.5 are “up”, while the BA.1 S protein has two “up” and one “down”. The BA.3 S protein displays increased heterogeneity, with the majority in the all “up” RBD state. The different conformations preferences of the S protein are consistent with their varied transmissibility. By analyzing the position of the glycan modification on Asn343, which is located at the S309 epitopes, we have uncovered the underlying immune evasion mechanism of the Omicron subvariants. Our findings provide a molecular basis of high infectivity and immune evasion of Omicron subvariants, thereby offering insights into potential therapeutic interventions against SARS-CoV-2 variants. Full article

(This article belongs to the Special Issue The Secret Life of ACE2 as a Receptor for the Coronaviruses)

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19 pages, 3395 KiB

Open AccessArticle

Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects

by Chia-Yin Lee, Anh Thuc Nguyen, Ly Hien Doan, Li-Wei Chu, Chih-Hung Chang, Hui-Kang Liu, I-Lin Lee, Teng-Hsu Wang, Jin-Mei Lai, Shih-Ming Tsao, Hsiu-Jung Liao, Yueh-Hsin Ping and Chi-Ying F. Huang

Viruses 2023, 15(3), 641; https://doi.org/10.3390/v15030641 - 27 Feb 2023

Cited by 2 | Viewed by 2244

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health. In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells. Full article

(This article belongs to the Special Issue The Secret Life of ACE2 as a Receptor for the Coronaviruses)

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Review

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14 pages, 2120 KiB

Open AccessReview

Molecular Imaging of ACE2 Expression in Infectious Disease and Cancer

by Zhiyao Li, Abbie Hasson, Lasya Daggumati, Hanwen Zhang and Daniel L. J. Thorek

Viruses 2023, 15(10), 1982; https://doi.org/10.3390/v15101982 - 23 Sep 2023

Viewed by 1185

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a cell-surface receptor that plays a critical role in the pathogenesis of SARS-CoV-2 infection. Through the use of ligands engineered for the receptor, ACE2 imaging has emerged as a valuable tool for preclinical and clinical research. These can be used to visualize the expression and distribution of ACE2 in tissues and cells. A variety of techniques including optical, magnetic resonance, and nuclear medicine contrast agents have been developed and employed in the preclinical setting. Positron-emitting radiotracers for highly sensitive and quantitative tomography have also been translated in the context of SARS-CoV-2-infected and control patients. Together this information can be used to better understand the mechanisms of SARS-CoV-2 infection, the potential roles of ACE2 in homeostasis and disease, and to identify potential therapeutic modulators in infectious disease and cancer. This review summarizes the tools and techniques to detect and delineate ACE2 in this rapidly expanding field. Full article

(This article belongs to the Special Issue The Secret Life of ACE2 as a Receptor for the Coronaviruses)

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