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1.
Libyan J Med ; 17(1): 2054111, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1752028

ABSTRACT

Vitamins (Vit) C and D are widely used as immunogenic supplements among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. The SAR-CoV-2 virus enters into the pulmonary endothelial cells through attachment to angiotensin converting enzyme 2 receptor (Ace2) and the proteolytic activity of Cathepsin L (Ctsl) and transmembrane serine protease 2 (Tmprss2) enzymes. This study aimed to determine the influence of Vit C and D on the mRNA expression of Ace2, Tmprss2, and Ctsl genes in the mouse lungs. Vitamins C and D were administrated to different groups of mice through intra-peritoneal route in doses equivalent to human for 30 days. Then, the mRNA expression of SARS-CoV-2 entry gene was analyzed using qRT-PCR. It is found that Vit D, but not C, upregulated significantly (P < 0.05) the mRNA expression of Ace2 by more than six folds, while downregulated the expression of Ctsl and Tmprss2 genes by 2.8 and 2.2 folds, respectively. It can be concluded from this study that Vit D alters the mRNA expression of Ace2, Tmprss, and Ctsl genes in the mouse lungs. This finding can help us in understanding, at least in part, the molecular influence of Vit D on genes involved in the entry of SARS-CoV-2 into the cells.


Subject(s)
COVID-19 , Serine Proteases , Angiotensin-Converting Enzyme 2 , Animals , Ascorbic Acid/metabolism , Ascorbic Acid/pharmacology , Cathepsin L/genetics , Cathepsin L/metabolism , Endothelial Cells , Humans , Lung/metabolism , Mice , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/metabolism , SARS-CoV-2 , Serine Proteases/metabolism , Vitamins
2.
Int J Mol Sci ; 22(16)2021 Aug 10.
Article in English | MEDLINE | ID: covidwho-1662670

ABSTRACT

Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) to restore the supply of oxygen to tissues and cells. Activated HIF-1α translocates into the nucleus and binds to hypoxia response elements to promote the transcription of target genes. Cathepsin L (CTSL) is a lysosomal protease that degrades cellular proteins via the endolysosomal pathway. In this study, we attempted to determine if CTSL is a hypoxia responsive target gene of HIF-1α, and decipher its role in melanocytes in association with the autophagic pathway. The results of our luciferase reporter assay showed that the expression of CTSL is transcriptionally activated through the binding of HIF1-α at its promoter. Under autophagy-inducing starvation conditions, HIF-1α and CTSL expression is highly upregulated in melan-a cells. The mature form of CTSL is closely involved in melanosome degradation through lysosomal activity upon autophagosome-lysosome fusion. The inhibition of conversion of pro-CTSL to mature CTSL leads to the accumulation of gp100 and tyrosinase in addition to microtubule-associated protein 1 light chain 3 (LC3) II, due to decreased lysosomal activity in the autophagic pathway. In conclusion, we have identified that CTSL, a novel target of HIF-1α, participates in melanosome degradation in melanocytes through lysosomal activity during autophagosome-lysosome fusion.


Subject(s)
Cathepsin L/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Melanosomes/metabolism , Animals , Cathepsin L/genetics , Cell Hypoxia/genetics , Cells, Cultured , Gene Expression Regulation , Melanocytes/metabolism , Mice , NIH 3T3 Cells
3.
Epigenomics ; 14(3): 153-162, 2022 02.
Article in English | MEDLINE | ID: covidwho-1622527

ABSTRACT

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.


Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.


Subject(s)
COVID-19/genetics , Dioxygenases/genetics , Epigenesis, Genetic , Histone Demethylases/genetics , Histones/genetics , Nuclear Proteins/genetics , Protein Processing, Post-Translational , Smoking/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/virology , Cathepsin D/genetics , Cathepsin D/metabolism , Cathepsin L/genetics , Cathepsin L/metabolism , Dioxygenases/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Methylation , Neuropilin-1/genetics , Neuropilin-1/metabolism , Neuropilin-2/genetics , Neuropilin-2/metabolism , Nuclear Proteins/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E/metabolism , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Smoking/metabolism , Smoking/pathology , Virus Internalization
4.
Emerg Microbes Infect ; 11(1): 182-194, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1550502

ABSTRACT

The ubiquitously-expressed proteolytic enzyme furin is closely related to the pathogenesis of SARS-CoV-2 and therefore represents a key target for antiviral therapy. Based on bioinformatic analysis and pseudovirus tests, we discovered a second functional furin site located in the spike protein. Furin still increased the infectivity of mutated SARS-CoV-2 pseudovirus in 293T-ACE2 cells when the canonical polybasic cleavage site (682-686) was deleted. However, K814A mutation eliminated the enhancing effect of furin on virus infection. Furin inhibitor prevented infection by 682-686-deleted SARS-CoV-2 in 293T-ACE2-furin cells, but not the K814A mutant. K814A mutation did not affect the activity of TMPRSS2 and cathepsin L but did impact the cleavage of S2 into S2' and cell-cell fusion. Additionally, we showed that this functional furin site exists in RaTG13 from bat and PCoV-GD/GX from pangolin. Therefore, we discovered a new functional furin site that is pivotal in promoting SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Cathepsin L/metabolism , Furin/metabolism , SARS-CoV-2/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/genetics , Animals , Cathepsin L/genetics , Cell Fusion , Chiroptera , Furin/genetics , Gene Expression , HEK293 Cells , Humans , Mice , Mice, Transgenic , Mutation , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/metabolism
5.
PLoS One ; 16(8): e0256141, 2021.
Article in English | MEDLINE | ID: covidwho-1362089

ABSTRACT

SARS-CoV-2 requires serine protease, transmembrane serine protease 2 (TMPRSS2), and cysteine proteases, cathepsins B, L (CTSB/L) for entry into host cells. These host proteases activate the spike protein and enable SARS-CoV-2 entry. We herein performed genomic-guided gene set enrichment analysis (GSEA) to identify upstream regulatory elements altering the expression of TMPRSS2 and CTSB/L. Further, medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 and CTSB/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Next, we analyzed drug-gene and gene-gene interaction networks using 809 human targets of SARS-CoV-2 proteins. The network results indicate that estradiol interacts with 370 (45%) and retinoic acid interacts with 251 (31%) human proteins. Interestingly, a combination of estradiol and retinoic acid interacts with 461 (56%) of human proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggests that both the drugs bind to TMPRSS2 and CTSL with the nanomolar to low micromolar affinity. The results suggest that these drugs can simultaneously target both the entry pathways of SARS-CoV-2 and thus can be considered as a potential treatment option for COVID-19.


Subject(s)
Cathepsin B/genetics , Cathepsin L/genetics , Estradiol/pharmacology , Genomics/methods , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Tretinoin/pharmacology , Cathepsin B/chemistry , Cathepsin L/chemistry , Databases, Genetic , Gene Expression Regulation, Enzymologic/drug effects , Gene Regulatory Networks/drug effects , Host-Pathogen Interactions , Humans , Models, Molecular , Molecular Docking Simulation , Protein Conformation , Protein Interaction Maps/drug effects , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Internalization/drug effects
6.
Viral Immunol ; 34(5): 352-357, 2021 06.
Article in English | MEDLINE | ID: covidwho-1343610

ABSTRACT

Intense immunological dysregulation including immune cell lesions has been characteristically observed in severe cases of coronavirus disease-2019 (COVID-19), for which molecular mechanisms are not properly understood. A study of physiological expressions of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) host cell entry-related factors in immune system components may help explain molecular mechanisms involved in COVID-19 immunopathology. We analyzed transcriptomic and proteomic expression metadata for SARS-CoV-2 host cell entry receptor ACE2 and entry associated proteases (TMPRSS2, CTSL, and FURIN) in silico across immune system components including the blood lineage cells. ACE2 was not detected in any of the studied immune cell components; however, varying transcriptomic and proteomic expressions were observed for TMPRSS2, CTSL, and FURIN. Nondetectable expressions of SARS-CoV-2 host cell entry receptor ACE2 in immune system components or blood lineage cells indicate it does not mediate immune cell lesions in COVID-19. Alternative mechanisms need to be explored for COVID-19 immunopathogenesis.


Subject(s)
COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/immunology , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , Cathepsin L/genetics , Furin/genetics , Healthy Volunteers , Humans , Immune System , Metadata , Proteomics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Transcriptome
7.
Nat Med ; 27(3): 546-559, 2021 03.
Article in English | MEDLINE | ID: covidwho-1319033

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/physiology , Sequence Analysis, RNA/statistics & numerical data , Single-Cell Analysis/statistics & numerical data , Virus Internalization , Adult , Aged , Aged, 80 and over , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Datasets as Topic/statistics & numerical data , Demography , Female , Gene Expression Profiling/statistics & numerical data , Humans , Lung/metabolism , Lung/virology , Male , Middle Aged , Organ Specificity/genetics , Respiratory System/metabolism , Respiratory System/virology , Sequence Analysis, RNA/methods , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis/methods
8.
J Virol ; 95(15): e0032721, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1305507

ABSTRACT

The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains; previously C6orf106) was identified as a proviral factor for Hendra virus infection and was recently characterized to function as an inhibitor of type I interferon expression. Here, we have utilized transcriptome sequencing (RNA-seq) to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of Caco-2 cells. We find that inhibition of ILRUN expression by RNA interference alters transcription profiles of numerous cellular pathways, including upregulation of the SARS-CoV-2 entry receptor ACE2 and several other members of the renin-angiotensin aldosterone system. In addition, transcripts of the SARS-CoV-2 coreceptors TMPRSS2 and CTSL were also upregulated. Inhibition of ILRUN also resulted in increased SARS-CoV-2 replication, while overexpression of ILRUN had the opposite effect, identifying ILRUN as a novel antiviral factor for SARS-CoV-2 replication. This represents, to our knowledge, the first report of ILRUN as a regulator of the renin-angiotensin-aldosterone system (RAAS). IMPORTANCE There is no doubt that the current rapid global spread of COVID-19 has had significant and far-reaching impacts on our health and economy and will continue to do so. Research in emerging infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is growing rapidly, with new breakthroughs in the understanding of host-virus interactions to assist with the development of innovative and exciting therapeutic strategies. Here, we present the first evidence that modulation of the human protein-coding gene ILRUN functions as an antiviral factor for SARS-CoV-2 infection, likely through its newly identified role in regulating the expression of SARS-CoV-2 entry receptors ACE2, TMPRSS2, and CTSL. These data improve our understanding of biological pathways that regulate host factors critical to SARS-CoV-2 infection, contributing to the development of antiviral strategies to deal with the current SARS-CoV-2 pandemic.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/metabolism , Down-Regulation , Gene Expression Regulation, Enzymologic , Neoplasm Proteins/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Caco-2 Cells , Cathepsin L/biosynthesis , Cathepsin L/genetics , Chlorocebus aethiops , Humans , Neoplasm Proteins/genetics , Renin-Angiotensin System , SARS-CoV-2/genetics , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Vero Cells
9.
Int J Mol Sci ; 22(9)2021 Apr 25.
Article in English | MEDLINE | ID: covidwho-1202187

ABSTRACT

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.


Subject(s)
COVID-19/pathology , Hyperandrogenism/pathology , Polycystic Ovary Syndrome/pathology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/urine , Animals , Blood Glucose/analysis , Body Weight/drug effects , COVID-19/complications , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Dihydrotestosterone/pharmacology , Female , Humans , Kidney/metabolism , Mice , Mice, Inbred C57BL , Polycystic Ovary Syndrome/complications , SARS-CoV-2/isolation & purification , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Up-Regulation/drug effects , Virus Internalization
10.
Signal Transduct Target Ther ; 6(1): 134, 2021 03 27.
Article in English | MEDLINE | ID: covidwho-1152831

ABSTRACT

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/metabolism , Cathepsin L , Cysteine Proteinase Inhibitors/pharmacology , Drug Development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Adolescent , Adult , Aged , Animals , COVID-19/drug therapy , COVID-19/genetics , Cathepsin L/antagonists & inhibitors , Cathepsin L/genetics , Cathepsin L/metabolism , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
11.
Nat Med ; 27(3): 546-559, 2021 03.
Article in English | MEDLINE | ID: covidwho-1114717

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/physiology , Sequence Analysis, RNA/statistics & numerical data , Single-Cell Analysis/statistics & numerical data , Virus Internalization , Adult , Aged , Aged, 80 and over , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Datasets as Topic/statistics & numerical data , Demography , Female , Gene Expression Profiling/statistics & numerical data , Humans , Lung/metabolism , Lung/virology , Male , Middle Aged , Organ Specificity/genetics , Respiratory System/metabolism , Respiratory System/virology , Sequence Analysis, RNA/methods , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis/methods
12.
Sci Rep ; 11(1): 4533, 2021 02 25.
Article in English | MEDLINE | ID: covidwho-1104538

ABSTRACT

Multiple studies have reported a doubling in risk of Coronavirus Disease-2019 (COVID-19) among cancer patients. Here, we examine the potential biological rationale behind this recurrent epidemiological observation. By leveraging large-scale genome-wide transcriptional data of normal and malignant tissues from adults and children, we found evidence of increased expression of SARS-CoV-2 viral entry genes in the cancer state, particularly in respiratory, gastrointestinal, and genitourinary tract tissues, with decreased expression in pediatric vs. adult samples. Additionally, by interrogating the temporal effects of radiotherapy on human peripheral blood mononuclear and mucosal cells, we observed important treatment-related alterations in host innate immunity, specifically type I interferon responses. Overall, cancers enhance expression of critical viral entry genes, and innate viral defenses can be dysregulated transiently during radiation treatments. These factors may contribute to the observed increased susceptibility to SARS-CoV-2 entry and severity of COVID-19 in cancer patients.


Subject(s)
COVID-19/complications , Immunity, Innate , Neoplasms/complications , SARS-CoV-2/physiology , Virus Internalization , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , COVID-19/genetics , COVID-19/immunology , Cathepsin L/genetics , Cathepsin L/immunology , Child , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/radiotherapy , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Severity of Illness Index
13.
Cell Res ; 31(4): 395-403, 2021 04.
Article in English | MEDLINE | ID: covidwho-1091494

ABSTRACT

The upcoming flu season in the Northern Hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental coinfection with influenza A virus (IAV) and either pseudotyped or live SARS-CoV-2 virus, we found that IAV preinfection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, in vivo, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice coinfected with IAV. Moreover, such enhancement of SARS-CoV-2 infectivity was not observed with several other respiratory viruses, likely due to a unique feature of IAV to elevate ACE2 expression. This study illustrates that IAV has a unique ability to aggravate SARS-CoV-2 infection, and thus, prevention of IAV infection is of great significance during the COVID-19 pandemic.


Subject(s)
COVID-19/pathology , Coinfection/pathology , Influenza A virus/physiology , Orthomyxoviridae Infections/pathology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/deficiency , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Cell Line , Coinfection/virology , Humans , Influenza A virus/isolation & purification , Lung/pathology , Mice , Mice, Transgenic , Orthomyxoviridae Infections/virology , RNA, Guide/metabolism , SARS-CoV-2/isolation & purification , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Severity of Illness Index , Viral Load , Virus Internalization
14.
PLoS One ; 15(12): e0243959, 2020.
Article in English | MEDLINE | ID: covidwho-1067398

ABSTRACT

There has been significant concern regarding fertility and reproductive outcomes during the SARS-CoV2 pandemic. Recent data suggests a high concentration of SARS-Cov2 receptors, ACE2 or TMPRSS2, in nasal epithelium and cornea, which explains person-to-person transmission. We investigated the prevalence of SARS-CoV2 receptors among reproductive tissues by exploring the single-cell sequencing datasets from uterus, myometrium, ovary, fallopian tube, and breast epithelium. We did not detect significant expression of either ACE2 or TMPRSS2 in the normal human myometrium, uterus, ovaries, fallopian tube, or breast. Furthermore, none of the cell types in the female reproductive organs we investigated, showed the co-expression of ACE2 with proteases, TMPRSS2, Cathepsin B (CTSB), and Cathepsin L (CTSL) known to facilitate the entry of SARS2-CoV2 into the host cell. These results suggest that myometrium, uterus, ovaries, fallopian tube, and breast are unlikely to be susceptible to infection by SARS-CoV2.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Cathepsin B/genetics , Cathepsin L/genetics , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/metabolism , Breast/metabolism , Breast/virology , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Epithelium/metabolism , Epithelium/virology , Fallopian Tubes/metabolism , Fallopian Tubes/virology , Female , Fertility/genetics , High-Throughput Nucleotide Sequencing , Humans , Myometrium/metabolism , Myometrium/virology , Ovary/metabolism , Ovary/virology , RNA, Viral/genetics , RNA, Viral/isolation & purification , Reproductive Tract Infections/genetics , Reproductive Tract Infections/virology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Single-Cell Analysis , Uterus/metabolism , Uterus/virology
15.
Hereditas ; 158(1): 4, 2021 Jan 04.
Article in English | MEDLINE | ID: covidwho-1067345

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) has spread rapidly around the world. In addition to common respiratory symptoms such as cough and fever, some patients also have cardiac injury, however, the mechanism of cardiac injury is not clear. In this study, we analyzed the RNA expression atlases of angiotensin-converting enzyme 2(ACE2), cathepsin B (CTSB) and cathepsin L (CTSL) in the human embryonic heart at single-cell resolution. RESULTS: The results showed that ACE2 was preferentially enriched in cardiomyocytes. Interestingly, serine protease transmembrane serine protease 2 (TMPRSS2) had less expression in cardiomyocytes, but CTSB and CTSL, which belonged to cell protease, could be found to be enriched in cardiomyocytes. The results of enrichment analysis showed that differentially expressed genes (DEGs) in ACE2-positive cardiomyocytes were mainly enriched in the processes of cardiac muscle contraction, regulation of cardiac conduction, mitochondrial respiratory chain, ion channel binding, adrenergic signaling in cardiomyocytes and viral transcription. CONCLUSIONS: Our study suggests that both atrial and ventricular cardiomyocytes are potentially susceptible to severe acute respiratory syndrome coronavirus-2(SARS-CoV-2), and SARS-CoV-2 may enter ventricular cardiomyocytes using CTSB/CTSL for S protein priming. This may be the partial cellular mechanism of cardiac injury in patients with COVID-19.


Subject(s)
COVID-19/prevention & control , Gene Expression Regulation, Developmental , Heart/embryology , Myocytes, Cardiac/metabolism , SARS-CoV-2/genetics , Single-Cell Analysis/methods , Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , COVID-19/virology , Cathepsin B/genetics , Cathepsin L/genetics , Gene Ontology , Humans , Myocytes, Cardiac/cytology , Myocytes, Cardiac/virology , Pandemics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Signal Transduction/genetics
16.
Curr Top Med Chem ; 21(7): 571-596, 2021.
Article in English | MEDLINE | ID: covidwho-1034909

ABSTRACT

Even after one year of its first outbreak reported in China, the coronavirus disease 2019 (COVID-19) pandemic is still sweeping the World, causing serious infections and claiming more fatalities. COVID-19 is caused by the novel coronavirus SARS-CoV-2, which belongs to the genus Betacoronavirus (ß-CoVs), which is of greatest clinical importance since it contains many other viruses that cause respiratory disease in humans, including OC43, HKU1, SARS-CoV, and MERS. The spike (S) glycoprotein of ß-CoVs is a key virulence factor in determining disease pathogenesis and host tropism, and it also mediates virus binding to the host's receptors to allow viral entry into host cells, i.e., the first step in virus lifecycle. Viral entry inhibitors are considered promising putative drugs for COVID-19. Herein, we mined the biomedical literature for viral entry inhibitors of other coronaviruses, with special emphasis on ß-CoVs entry inhibitors. We also outlined the structural features of SARS-CoV-2 S protein and how it differs from other ß-CoVs to better understand the structural determinants of S protein binding to its human receptor (ACE2). This review highlighted several promising viral entry inhibitors as potential treatments for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Protease Inhibitors/chemistry , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/virology , Cathepsin L/antagonists & inhibitors , Cathepsin L/chemistry , Cathepsin L/genetics , Cathepsin L/metabolism , Gene Expression , Humans , Phytochemicals/chemistry , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , Protease Inhibitors/isolation & purification , Protease Inhibitors/pharmacology , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/chemistry , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/isolation & purification , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
17.
Front Cell Infect Microbiol ; 10: 589505, 2020.
Article in English | MEDLINE | ID: covidwho-1000069

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) is the most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by a robust immunological response leading to ARDS and multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. CatL is a lysosomal enzyme that participates in numerous physiological processes, including apoptosis, antigen processing, and extracellular matrix remodeling. CatL is implicated in pathological conditions like invasion and metastasis of tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, and other diseases. CatL expression is up-regulated during chronic inflammation and is involved in degrading extracellular matrix, an important process for SARS-CoV-2 to enter host cells. In addition, CatL is probably involved in processing SARS-CoV-2 spike protein. As its inhibition is detrimental to SARS-CoV-2 infection and possibly exit from cells during late stages of infection, CatL could have been considered a valuable therapeutic target. Therefore, we describe here some drugs already in the market with potential CatL inhibiting capacity that could be used to treat COVID-19 patients. In addition, we discuss the possible role of host genetics in the etiology and spreading of the disease.


Subject(s)
COVID-19/complications , Cathepsin L/physiology , Pandemics , Respiratory Distress Syndrome/enzymology , SARS-CoV-2/physiology , Acute Kidney Injury/etiology , Amantadine/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/epidemiology , Cathepsin L/antagonists & inhibitors , Cathepsin L/genetics , Chloroquine/therapeutic use , Cysteine Proteinase Inhibitors/therapeutic use , Genetic Predisposition to Disease , Heparin/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lysosomes/enzymology , Molecular Targeted Therapy , Receptors, Virus/metabolism , Respiratory Distress Syndrome/etiology , SARS-CoV-2/ultrastructure , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Teicoplanin/therapeutic use , Virus Internalization
18.
Aging (Albany NY) ; 12(22): 22370-22389, 2020 11 20.
Article in English | MEDLINE | ID: covidwho-967740

ABSTRACT

SARS-coronavirus 2 (SARS-CoV-2) has been spreading widely and posing an international challenge for both healthcare and society. At present, cancer has been identified as an individual risk factor for COVID-19. Angiotensin converting enzyme 2 (ACE2) and Cathepsin L/Cathepsin B (CTSL/B), which act as the receptor and entry-associated proteases of SARS-CoV-2 respectively, are pivotal for SARS-CoV-2 infection. To investigate the possible SARS-CoV-2 infection risk of pan-cancer, we analyzed the genetic alterations, RNA expression, DNA methylation, and the association with immune subtypes of ACE2 and CTSL/B with the prognosis in pan-cancer. Results showed the upregulation of CTSL/B and ACE2 in Pancreatic adenocarcinoma (PAAD) and Stomach adenocarcinoma (STAD) and demonstrated a positive correlation between copy number alteration (CNA) and gene expression for CTSB in PAAD and STAD. Hypomethylation and a negative correlation of gene expression and methylation for CTSB were detected in PAAD. In addition, ACE2 and CTSL/B are overexpressed in the IFN-gamma immune subtype of ovarian serous Cystadenocarcinoma (OV), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and Bladder urothelial carcinoma (BLCA). Our study presents a bioinformatics assessment for the potential risk of SARS-CoV-2 infection in pan-cancer.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , Cathepsin B/genetics , Cathepsin L/genetics , Neoplasms/genetics , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/virology , Cathepsin B/immunology , Cathepsin L/immunology , Computational Biology , DNA Methylation , Epigenesis, Genetic , Epigenomics , Female , Gene Expression Regulation, Neoplastic/immunology , Genetic Variation , Humans , Mutation , Neoplasms/complications , Neoplasms/immunology , Pandemics , Risk Assessment , Risk Factors , SARS-CoV-2/pathogenicity , Transcriptome , Virus Internalization
19.
Molecules ; 25(17)2020 Aug 22.
Article in English | MEDLINE | ID: covidwho-727433

ABSTRACT

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/drug effects , Cathepsin L/chemistry , Phytochemicals/chemistry , Protease Inhibitors/chemistry , Receptors, Virus/chemistry , Serine Endopeptidases/chemistry , Amino Acid Sequence , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Betacoronavirus/pathogenicity , Binding Sites , COVID-19 , Cathepsin L/antagonists & inhibitors , Cathepsin L/genetics , Cathepsin L/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Coumarins/chemistry , Coumarins/isolation & purification , Coumarins/pharmacology , Gene Expression , High-Throughput Screening Assays , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , India , Molecular Docking Simulation , Molecular Dynamics Simulation , Monosaccharides/chemistry , Monosaccharides/isolation & purification , Monosaccharides/pharmacology , Pandemics , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protease Inhibitors/isolation & purification , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quinazolines/chemistry , Quinazolines/isolation & purification , Quinazolines/pharmacology , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Thermodynamics , Virus Internalization/drug effects
20.
Life Sci ; 260: 118313, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-725734

ABSTRACT

BACKGROUND: The prevalence and mortality of the outbreak of the COVID-19 pandemic show marked geographic variation. The presence of several subtypes of the coronavirus and the genetic differences in the populations could condition that variation. Thus, the objective of this study was to propose variants in genes that encode proteins related to the SARS-CoV-2 entry into the host cells as possible targets for genetic associations studies. METHODS: The allelic frequencies of the polymorphisms in the ACE2, TMPRSS2, TMPRSS11A, cathepsin L (CTSL), and elastase (ELANE) genes were obtained in four populations from the American, African, European, and Asian continents reported in the 1000 Genome Project. Moreover, we evaluated the potential biological effect of these variants using different web-based tools. RESULTS: In the coding sequences of these genes, we detected one probably-damaging polymorphism located in the TMPRSS2 gene (rs12329760) that produces a change of amino acid. Furthermore, forty-eight polymorphisms with possible functional consequences were detected in the non-coding sequences of the following genes: three in ACE2, seventeen in TMPRSS2, ten in TMPRSS11A, twelve in ELANE, and six in CTSL. These polymorphisms produce binding sites for transcription factors and microRNAs. The minor allele frequencies of these polymorphisms vary in each community; indeed, some of them are high in specific populations. CONCLUSION: In summary, using data of the 1000 Genome Project and web-based tools, we propose some polymorphisms, which, depending on the population, could be used for genetic association studies.


Subject(s)
Betacoronavirus , Cathepsin L/genetics , Coronavirus Infections/genetics , Leukocyte Elastase/genetics , Membrane Proteins/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Polymorphism, Genetic , Serine Endopeptidases/genetics , Serine Proteases/genetics , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Frequency , Genetic Association Studies , Humans , Linkage Disequilibrium , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2
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