scholarly journals TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 384
Author(s):  
Mai Kishimoto ◽  
Kentaro Uemura ◽  
Takao Sanaki ◽  
Akihiko Sato ◽  
William W. Hall ◽  
...  
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Spike Protein ◽  
Tissue Tropism ◽  
Type Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Exogenous Expression ◽  
Transmembrane Serine Protease ◽  
The Impact

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.

scholarly journals The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

2021 ◽  
Vol 22 (15) ◽  
pp. 8226
Author(s):  
John Tsu-An Hsu ◽  
Chih-Feng Tien ◽  
Guann-Yi Yu ◽  
Santai Shen ◽  
Yi-Hsuan Lee ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Viral Entry ◽  
Negative Impact ◽  
Spike Protein ◽  
Infection Model ◽  
Converting Enzyme ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
People With Dementia ◽  
The Impact

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

scholarly journals Gene of the month: TMPRSS2 (transmembrane serine protease 2)

2020 ◽  
Vol 73 (12) ◽  
pp. 773-776 ◽  
Author(s):  
Michelle Thunders ◽  
Brett Delahunt
Keyword(s):  
Serine Protease ◽  
Viral Entry ◽  
Fusion Gene ◽  
Related Gene ◽  
Diverse Range ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Spread ◽  
Transmembrane Serine Protease ◽  
Oncogenic Transcription Factor

Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.

scholarly journals Inhibition of SARS-CoV-2 viral entry upon blocking N- and O-glycan elaboration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Qi Yang ◽  
Thomas A Hughes ◽  
Anju Kelkar ◽  
Xinheng Yu ◽  
Kai Cheng ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Multiple Roles ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Mechanistic Studies ◽  
Post Translational Modification ◽  
Minor Contribution ◽  
Chemical Inhibitors ◽  
The Impact

The Spike protein of SARS-CoV-2, its receptor-binding domain (RBD), and its primary receptor ACE2 are extensively glycosylated. The impact of this post-translational modification on viral entry is yet unestablished. We expressed different glycoforms of the Spike-protein and ACE2 in CRISPR-Cas9 glycoengineered cells, and developed corresponding SARS-CoV-2 pseudovirus. We observed that N- and O-glycans had only minor contribution to Spike-ACE2 binding. However, these carbohydrates played a major role in regulating viral entry. Blocking N-glycan biosynthesis at the oligomannose stage using both genetic approaches and the small molecule kifunensine dramatically reduced viral entry into ACE2 expressing HEK293T cells. Blocking O-glycan elaboration also partially blocked viral entry. Mechanistic studies suggest multiple roles for glycans during viral entry. Among them, inhibition of N-glycan biosynthesis enhanced Spike-protein proteolysis. This could reduce RBD presentation on virus, lowering binding to host ACE2 and decreasing viral entry. Overall, chemical inhibitors of glycosylation may be evaluated for COVID-19.

scholarly journals Energetics based epitope screening in SARS CoV-2 (COVID 19) spike glycoprotein by Immuno-informatic analysis aiming to a suitable vaccine development

2020 ◽  
Author(s):  
Amrita Banerjee ◽  
Dipannita Santra ◽  
Smarajit Maiti
Keyword(s):  
Vaccine Development ◽  
Spike Glycoprotein ◽  
Structure Quality ◽  
Angiotensin Converting Enzyme 2 ◽  
Mhc Ii ◽  
Good Target ◽  
Short Period ◽  
Recent Outbreak ◽  
Interpro Database

AbstractThe recent outbreak by SARS-CoV-2 has generated a chaos in global health and economy and claimed/infected a large number of lives. Closely resembling with SARS CoV, the present strain has manifested exceptionally higher degree of spreadability, virulence and stability possibly due to some unidentified mutations. The viral spike glycoprotein is very likely to interact with host Angiotensin-Converting Enzyme 2 (ACE2) and transmits its genetic materials and hijacks host machinery with extreme fidelity for self propagation. Few attempts have been made to develop a suitable vaccine or ACE2 blocker or virus-receptor inhibitor within this short period of time. Here, attempt was taken to develop some therapeutic and vaccination strategies with a comparison of spike glycoproteins among SARS-CoV, MERS-CoV and the SARS-CoV-2. We verified their structure quality (SWISS-MODEL, Phyre2, Pymol) topology (ProFunc), motifs (MEME Suite, GLAM2Scan), gene ontology based conserved domain (InterPro database) and screened several epitopes (SVMTrip) of SARS CoV-2 based on their energetics, IC50 and antigenicity with regard to their possible glycosylation and MHC/paratopic binding (Vaxigen v2.0, HawkDock, ZDOCK Server) effects. We screened here few pairs of spike protein epitopic regions and selected their energetic, IC50, MHC II reactivity and found some of those to be very good target for vaccination. A possible role of glycosylation on epitopic region showed profound effects on epitopic recognition. The present work might be helpful for the urgent development of a suitable vaccination regimen against SARS CoV-2.

scholarly journals Uremic Apelin and Leucocytic Angiotensin-Converting Enzyme 2 in CKD Patients

Toxins ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 742
Author(s):  
Bogusz Trojanowicz ◽  
Christof Ulrich ◽  
Matthias Girndt
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Healthy Controls ◽  
Converting Enzyme ◽  
Blood Pressure Lowering ◽  
Angiotensin Converting Enzyme 2 ◽  
Pressure Lowering ◽  
The Impact ◽  
Progression Of Atherosclerosis

Apelin peptides (APLN) serve as second substrates for angiotensin-converting enzyme 2 (ACE2) and, in contrast to angiotensin II (AngII), exert blood-pressure lowering and vasodilatation effects through binding to G-coupled APLN receptor (APLNR). ACE2-mediated cleavage of the APLN may reduce its vasodilatory effects, but decreased ACE2 may potentiate the hypotensive properties of APLN. The role of APLN in uremia is unclear. We investigated the correlations between serum-APLN, leucocytic APLNR, and ACE2 in 32 healthy controls (NP), 66 HD, and 24 CKD3–5 patients, and the impact of APLN peptides on monocytic behavior and ACE2 expression under uremic conditions in vitro. We observed that serum APLN and leucocytic APLNR or SLCO2B1 were significantly elevated in uremic patients and correlated with decreased ACE2 on uremic leucocytes. APLN-treated THP-1 monocytes revealed significantly increased APLNR and ACE2, and reduced TNFa, IL-6, and MCSF. Uremic toxins induced a dramatic increase of miR-421 followed by significant reduction of ACE2 transcripts, partially counteracted with APLN-13 and -36. APLN-36 triggered the most potent transmigration and reduction of endothelial adhesion. These results suggest that although APLN peptides may partly protect against the decay of monocytic ACE2 transcripts, uremic milieu is the most dominant modulator of local ACE2, and likely to contribute to the progression of atherosclerosis.

scholarly journals Is There a Link between Bisphenol A (BPA), a Key Endocrine Disruptor, and the Risk for SARS-CoV-2 Infection and Severe COVID-19?

2020 ◽  
Vol 9 (10) ◽  
pp. 3296
Author(s):  
Aeman Zahra ◽  
Cristina Sisu ◽  
Elisabete Silva ◽  
Sophie-Christine De Aguiar Greca ◽  
Harpal S. Randeva ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Potential Role ◽  
Metabolic Diseases ◽  
Endocrine Disrupting Chemicals ◽  
Angiotensin Converting Enzyme 2 ◽  
Endocrine Disrupting ◽  
Membrane Bound ◽  
Transmembrane Serine Protease ◽  
G Protein Coupled

Infection by the severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) is the causative agent of a new disease (COVID-19). The risk of severe COVID-19 is increased by certain underlying comorbidities, including asthma, cancer, cardiovascular disease, hypertension, diabetes, and obesity. Notably, exposure to hormonally active chemicals called endocrine-disrupting chemicals (EDCs) can promote such cardio-metabolic diseases, endocrine-related cancers, and immune system dysregulation and thus, may also be linked to higher risk of severe COVID-19. Bisphenol A (BPA) is among the most common EDCs and exerts its effects via receptors which are widely distributed in human tissues, including nuclear oestrogen receptors (ERα and ERβ), membrane-bound oestrogen receptor (G protein-coupled receptor 30; GPR30), and human nuclear receptor oestrogen-related receptor gamma. As such, this paper focuses on the potential role of BPA in promoting comorbidities associated with severe COVID-19, as well as on potential BPA-induced effects on key SARS-CoV-2 infection mediators, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Interestingly, GPR30 appears to exhibit greater co-localisation with TMPRSS2 in key tissues like lung and prostate, suggesting that BPA exposure may impact on the local expression of these SARS-CoV-2 infection mediators. Overall, the potential role of BPA on the risk and severity of COVID-19 merits further investigation.

scholarly journals Modeling the Molecular Impact of SARS-CoV-2 Infection on the Renin-Angiotensin System

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1367
Author(s):  
Fabrizio Pucci ◽  
Philippe Bogaerts ◽  
Marianne Rooman
Keyword(s):  
Renin Angiotensin System ◽  
Therapeutic Strategies ◽  
Spike Protein ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Pathogenic Mechanisms ◽  
Renin Angiotensin ◽  
Factors Associated ◽  
Ras Blockers ◽  
The Impact

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1–7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.

scholarly journals Cytoplasmic tail truncation of SARS-CoV-2 Spike protein enhances titer of pseudotyped vectors but masks the effect of the D614G mutation

2021 ◽  
Author(s):  
Hsu-Yu Chen ◽  
Chun Huang ◽  
Lu Tian ◽  
Xiaoli Huang ◽  
Chennan Zhang ◽  
...  
Keyword(s):  
Viral Entry ◽  
High Titer ◽  
Cytoplasmic Tail ◽  
Cell Types ◽  
Spike Protein ◽  
Tangential Flow Filtration ◽  
Tangential Flow ◽  
Protein Functions ◽  
Flow Filtration ◽  
The Impact

The high pathogenicity of SARS-CoV-2 requires it to be handled under biosafety level 3 conditions. Consequently, Spike protein pseudotyped vectors are a useful tool to study viral entry and its inhibition, with retroviral, lentiviral (LV) and vesicular stomatitis virus (VSV) vectors the most commonly used systems. Methods to increase the titer of such vectors commonly include concentration by ultracentrifugation and truncation of the Spike protein cytoplasmic tail. However, limited studies have examined whether such a modification also impacts the protein’s function. Here, we optimized concentration methods for SARS-CoV-2 Spike pseudotyped VSV vectors, finding that tangential flow filtration produced vectors with more consistent titers than ultracentrifugation. We also examined the impact of Spike tail truncation on transduction of various cell types and sensitivity to convalescent serum neutralization. We found that tail truncation increased Spike incorporation into both LV and VSV vectors and resulted in enhanced titers, but had no impact on sensitivity to convalescent serum inhibition. In addition, we analyzed the effect of the D614G mutation, which became a dominant SARS-CoV-2 variant early in the pandemic. Our studies revealed that, similar to the tail truncation, D614G independently increases Spike incorporation and vector titers, but that this effect is masked by also including the cytoplasmic tail truncation. Therefore, the use of full-length Spike protein, combined with tangential flow filtration, is recommended as a method to generate high titer pseudotyped vectors that retain native Spike protein functions.

scholarly journals COVID-19 and androgen-targeted therapy for prostate cancer patients

2020 ◽  
Vol 27 (9) ◽  
pp. R281-R292 ◽  
Author(s):  
Neil A Bhowmick ◽  
Jillian Oft ◽  
Tanya Dorff ◽  
Sumanta Pal ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Viral Entry ◽  
Host Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Cancer Management ◽  
Signaling Inhibitors ◽  
Androgen Regulation ◽  
Androgen Suppression ◽  
Transmembrane Serine Protease ◽  
Significant Disease

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.

scholarly journals Cell-Mimicking Nanodecoys Protect Lung Cells by Neutralization of SARS-CoV-2 Spike Proteins

2020 ◽  
Author(s):  
Zhenhua Li ◽  
Phuong-Uyen C. Dinh ◽  
Kristen D. Popowski ◽  
Halle Lutz ◽  
Zhenzhen Wang ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Spike Protein ◽  
Inhalation Therapy ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
Non Invasive ◽  
Global Pandemic ◽  
Integral Role

Abstract Coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has grown into a global pandemic, with no specific antiviral treatments or vaccines are yet approved. The viral receptor, angiotensin-converting enzyme 2 (ACE2), has been demonstrated to play an integral role in the pathogenesis of SARS-CoV-2, necessary for host cell viral entry. Inspired by this, we synthesized ACE2 nanodecoys from human lung spheroid cells (LSCs) capable of binding the Spike protein as a potential neutralization agent for SARS-CoV-2. Our results show LSC-nanodecoys has a high affinity and neutralization efficiency to both spike protein and chemically synthesized SARS-CoV-2 mimics. In addition, non-invasive inhalation therapy in mice showed successful delivery of the nanodecoy to the lungs, as well as in-vivo retention of the nanodecoys over 72 hours after a single administration. Furthermore, inhalation of nanodecoy accelerated the clearance of SARS-CoV-2 mimics from the lung and did not cause toxicity.

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