scholarly journals LRRC15 is an inhibitory receptor blocking SARS-CoV-2 spike-mediated entry in trans

2021 ◽  
Author(s):  
Jaewon Song ◽  
Ryan D Chow ◽  
Mario Pena-Hernandez ◽  
Li Zhang ◽  
Skylar A Loeb ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Cell Types ◽  
Protective Role ◽  
Receptor Binding Domain ◽  
Inhibitory Receptor ◽  
In Trans ◽  
Entry Receptor ◽  
Crispr Activation

SARS-CoV-2 infection is mediated by the entry receptor ACE2. Although attachment factors and co-receptors facilitating entry are extensively studied, cellular entry factors inhibiting viral entry are largely unknown. Using a surfaceome CRISPR activation screen, we identified human LRRC15 as an inhibitory receptor for SARS-CoV-2 entry. LRRC15 directly binds to the receptor-binding domain (RBD) of spike protein with a moderate affinity and inhibits spike-mediated entry. Analysis of human lung single cell RNA sequencing dataset reveals that expression of LRRC15 is primarily detected in fibroblasts and particularly enriched in pathological fibroblasts in COVID-19 patients. ACE2 and LRRC15 are not co-expressed in the same cell types in the lung. Strikingly, expression of LRRC15 in ACE2-negative cells blocks spike-mediated viral entry in ACE2+ cell in trans, suggesting a protective role of LRRC15 in a physiological context. Therefore, LRRC15 represents an inhibitory receptor for SARS-CoV-2 regulating viral entry in trans.

scholarly journals Coronavirus Disease (COVID)-19 and Diabetic Kidney Disease

2021 ◽  
Vol 14 (8) ◽  
pp. 751
Author(s):  
Swayam Prakash Srivastava ◽  
Rohit Srivastava ◽  
Subhash Chand ◽  
Julie E. Goodwin
Keyword(s):  
Kidney Disease ◽  
Viral Entry ◽  
Diabetic Kidney Disease ◽  
Thrombus Formation ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Protective Role ◽  
Kidney Cells ◽  
Diabetic Kidney

The present review describes COVID-19 severity in diabetes and diabetic kidney disease. We discuss the crucial effect of COVID-19-associated cytokine storm and linked injuries and associated severe mesenchymal activation in tubular epithelial cells, endothelial cells, and macrophages that influence neighboring cell homeostasis, resulting in severe proteinuria and organ fibrosis in diabetes. Altered microRNA expression disrupts cellular homeostasis and the renin-angiotensin-system, targets reno-protective signaling proteins, such as angiotensin-converting enzyme 2 (ACE2) and MAS1 receptor (MAS), and facilitates viral entry and replication in kidney cells. COVID-19-associated endotheliopathy that interacts with other cell types, such as neutrophils, platelets, and macrophages, is one factor that accelerates prethrombotic reactions and thrombus formation, resulting in organ failures in diabetes. Apart from targeting vital signaling through ACE2 and MAS, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are also associated with higher profibrotic dipeptidyl transferase-4 (DPP-4)-mediated mechanisms and suppression of AMP-activated protein kinase (AMPK) activation in kidney cells. Lowered DPP-4 levels and restoration of AMPK levels are organ-protective, suggesting a pathogenic role of DPP-4 and a protective role of AMPK in diabetic COVID-19 patients. In addition to standard care provided to COVID-19 patients, we urgently need novel drug therapies that support the stability and function of both organs and cell types in diabetes.

scholarly journals Emerging Roles for Browning of White Adipose Tissue in Prostate Cancer Malignant Behaviour

2021 ◽  
Vol 22 (11) ◽  
pp. 5560
Author(s):  
Alejandro Álvarez-Artime ◽  
Belén García-Soler ◽  
Rosa María Sainz ◽  
Juan Carlos Mayo
Keyword(s):  
Prostate Cancer ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Tumor Development ◽  
Cell Types ◽  
Protective Role ◽  
Bioactive Molecules ◽  
Brown Adipose ◽  
Endocrine Organs

In addition to its well-known role as an energy repository, adipose tissue is one of the largest endocrine organs in the organism due to its ability to synthesize and release different bioactive molecules. Two main types of adipose tissue have been described, namely white adipose tissue (WAT) with a classical energy storage function, and brown adipose tissue (BAT) with thermogenic activity. The prostate, an exocrine gland present in the reproductive system of most mammals, is surrounded by periprostatic adipose tissue (PPAT) that contributes to maintaining glandular homeostasis in conjunction with other cell types of the microenvironment. In pathological conditions such as the development and progression of prostate cancer, adipose tissue plays a key role through paracrine and endocrine signaling. In this context, the role of WAT has been thoroughly studied. However, the influence of BAT on prostate tumor development and progression is unclear and has received much less attention. This review tries to bring an update on the role of different factors released by WAT which may participate in the initiation, progression and metastasis, as well as to compile the available information on BAT to discuss and open a new field of knowledge about the possible protective role of BAT in prostate cancer.

scholarly journals ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

2020 ◽  
Vol 134 (22) ◽  
pp. 3047-3062
Author(s):  
Koichi Yamamoto ◽  
Hikari Takeshita ◽  
Hiromi Rakugi
Keyword(s):  
Skeletal Muscle ◽  
Transmembrane Protein ◽  
Renin Angiotensin System ◽  
Protective Role ◽  
Potential Contribution ◽  
Angiotensin Converting Enzyme 2 ◽  
Multiple Organs ◽  
Potential Association ◽  
Entry Receptor

Abstract Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin–angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

scholarly journals Protective Role of Flavonoids against Intestinal Pro-Inflammatory Effects of Silver Nanoparticles

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6610
Author(s):  
Ana T. Rufino ◽  
Ana Ramalho ◽  
Adelaide Sousa ◽  
José Miguel P. Ferreira de Oliveira ◽  
Paulo Freitas ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Protective Action ◽  
Cell Types ◽  
Protective Role ◽  
Toxic Effects ◽  
Oral Exposure ◽  
Dietary Flavonoids ◽  
Harmful Effects ◽  
Human Intestinal Cells

Silver nanoparticles (AgNP) have been increasingly incorporated into food-related and hygiene products for their unique antimicrobial and preservative properties. The consequent oral exposure may then result in unpredicted harmful effects in the gastrointestinal tract (GIT), which should be considered in the risk assessment and risk management of these materials. In the present study, the toxic effects of polyethyleneimine (PEI)-coated AgNP (4 and 19 nm) were evaluated in GIT-relevant cells (Caco-2 cell line as a model of human intestinal cells, and neutrophils as a model of the intestinal inflammatory response). This study also evaluated the putative protective action of dietary flavonoids against such harmful effects. The obtained results showed that AgNP of 4 and 19 nm effectively induced Caco-2 cell death by apoptosis with concomitant production of nitric oxide, irrespective of the size. It was also observed that AgNP induced human neutrophil oxidative burst. Interestingly, some flavonoids, namely quercetin and quercetagetin, prevented the deleterious effects of AgNP in both cell types. Overall, the data of the present study provide a first insight into the promising protective role of flavonoids against the potentially toxic effects of AgNP at the intestinal level.

scholarly journals IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

2020 ◽  
Author(s):  
Caterina Prelli Bozzo ◽  
Rayhane Nchioua ◽  
Meta Volcic ◽  
Jana Krüger ◽  
Sandra Heller ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Lung Cells ◽  
Therapeutic Approaches ◽  
Viral Pathogens ◽  
Virus Inhibition ◽  
Human Lung Cells

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

Glutathione S-transferases of human lung: Characterization and evaluation of the protective role of the α-class isozymes against lipid peroxidation

1992 ◽  
Vol 299 (2) ◽  
pp. 232-241 ◽  
Author(s):  
Sharad S. Singhal ◽  
Manju Saxena ◽  
Hassan Ahmad ◽  
Sanjay Awasthi ◽  
Abida K. Haque ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Human Lung ◽  
Protective Role ◽  
Glutathione S Transferases

Effect of ozone oxidative stress on chloride current in human lung cells: Chemical mediators and protective role of catalase

2017 ◽  
Vol 108 ◽  
pp. S45
Author(s):  
Rita Canella ◽  
Mascia Benedusi ◽  
Carlotta Cavicchio ◽  
Franco Cervellati ◽  
Marta Martini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Lung ◽  
Protective Role ◽  
Chloride Current ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Chemical Mediators

scholarly journals Enzalutamide, a prostate cancer therapeutic, downregulates TMPRSS2 in lung and reduces cellular entry of SARS-CoV-2

2021 ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
A. M. Isac ◽  
L. L. Yates ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Viral Entry ◽  
Human Lung ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Surface Proteins ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Transcription Factor Activation

Abstract The COVID-19 pandemic, caused by the novel human coronavirus SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. To determine therapeutic potential, we assessed uptake of SARS-CoV-2 Spike protein pseudotyped lentivirus and live SARS-CoV-2 into human lung cells and saw a significant reduction in viral entry and infection upon treatment with the antiandrogens enzalutamide and bicalutamide. In support of this new experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals Deletion of the Second Immunoglobulin-Like Domain of Nectin-1 Alters Its Intracellular Processing and Localization and Ability To Mediate Entry of Herpes Simplex Virus

2005 ◽  
Vol 79 (6) ◽  
pp. 3841-3845 ◽  
Author(s):  
Frank Struyf ◽  
Aileen E. Plate ◽  
Patricia G. Spear
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Adhesion ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Entry ◽  
Deletion Mutant ◽  
Intracellular Processing ◽  
Simplex Virus ◽  
Entry Receptor

ABSTRACT Nectin-1 is an immunoglobulin (Ig)-like entry receptor for herpes simplex virus (HSV). Like other nectins, nectin-1 forms dimers and mediates cell adhesion through interactions with other nectins. We constructed a second-domain deletion mutant of nectin-1 (nectin-1-Δ2) to examine the role of the second Ig-like domain in HSV entry. Nectin-1-Δ2 exhibited a severely reduced ability to mediate HSV entry and accumulated in the endoplasmic reticulum but retained the ability to interact with its HSV ligand, gD. The failure of nectin-1-Δ2 to mediate HSV entry probably resulted from its failure to be transported to a membrane targeted by HSV for viral entry.

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