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1.
Hypertension ; 76(5): 1526-1536, 2020 11.
Article in English | MEDLINE | ID: covidwho-2153220

ABSTRACT

ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.


Subject(s)
Coronavirus Infections/epidemiology , Disease Outbreaks/statistics & numerical data , Disease Progression , Heart Failure/enzymology , Heart Failure/physiopathology , Peptidyl-Dipeptidase A/blood , Pneumonia, Viral/epidemiology , Academic Medical Centers , Analysis of Variance , Angiotensin-Converting Enzyme 2 , Biomarkers/metabolism , COVID-19 , Cohort Studies , Coronavirus Infections/prevention & control , Female , Humans , Linear Models , Male , Middle Aged , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Prognosis , Proportional Hazards Models , Proteomics/methods , Retrospective Studies , Sensitivity and Specificity , Severity of Illness Index , United States
2.
Front Mol Biosci ; 7: 569414, 2020.
Article in English | MEDLINE | ID: covidwho-1793002

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) was first detected in patients with pneumonia in December 2019 in China and it spread rapidly to the rest of the world becoming a global pandemic. Several observational studies have reported that cancer is a risk factor for COVID-19. On the other hand, ACE2, a receptor for the SARS-CoV-2 virus, was found to be aberrantly expressed in many tumors. However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated. Here, we conducted a systematic analysis of the ACE2 expression profile across 31 types of tumors. METHODS: Distribution of ACE2 expression was analyzed using the GTEx, CCLE, TCGA pan-cancer databases. We evaluated the effect of ACE2 on clinical prognosis using the Kaplan-Meier survival plot and COX regression analysis. Correlation between ACE2 and immune infiltration levels was investigated in various cancer types. Additionally, the correlation between ACE2 and immune neoantigen, TMB, microsatellite instability, Mismatch Repair Genes (MMRs), HLA gene members, and DNA Methyltransferase (DNMT) was investigated. The frequency of ACE2 gene mutation in various tumors was analyzed. Functional enrichment analysis was conducted in various cancer types using the GSEA method. RESULTS: In normal tissues, ACE2 was highly expressed in almost all 31 organs tested. In cancer cell lines, the expression level of ACE2 was low to medium. Although aberrant expression was observed in most cancer types, high expression of ACE2 was not linked to OS, DFS, RFS, and DFI in most tumors in TCGA pan-cancer data. We found that ACE2 expression was significantly correlated with the infiltrating levels of macrophages and dendritic cells, CD4+ T cells, CD8+ T cells, and B cells in multiple tumors. A positive correlation between ACE2 expression and immune neoantigen, TMB, and microsatellite instability was found in multiple cancers. GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors. CONCLUSION: These findings suggest that ACE2 is not correlated with prognosis in most cancer types. However, elevated ACE2 is significantly correlated with immune infiltrating levels, including those of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in multiple cancers, especially in lung and breast cancer patients. These findings suggest that ACE2 may affect the tumor environment in cancer patients with COVID-19.

3.
Rev Med Virol ; 31(5): 1-12, 2021 09.
Article in English | MEDLINE | ID: covidwho-1575376

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumour necrosis factor-α-converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1-7), to balance the renin angiotensin system. Membrane-bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS-CoV-2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non-primed virus-sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II-angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , COVID-19/virology , Comorbidity , Humans , Peptide Fragments/metabolism , SARS-CoV-2/physiology
4.
Curr Drug Targets ; 22(16): 1832-1843, 2021.
Article in English | MEDLINE | ID: covidwho-1511929

ABSTRACT

ACE2 has long been known as an injury protective protein, which can protect against a variety of organ damage such as the heart, liver, kidney, and lung. Especially in cardiovascular diseases, as a negative regulator of RAAS, ACE2 is an extremely important protective factor that mainly plays a role by converting Ang II to Ang-(1-7). Nevertheless, with the recent outbreak of COVID-19, it is exposed that another identity of ACE2 is the entry receptor for SARS-CoV-2, which previously serves as the entry receptor for SARS. With the in-depth clinical research, it is found that the severity and susceptibility of COVID-19 are related to cardiovascular diseases, and SARS-CoV-2 binding to ACE2 receptor is also potentially associated with heart injury symptoms. Therefore, in this article, we mainly summarize the relationship between ACE2, COVID-19, and cardiovascular diseases/heart injury.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Cardiovascular Diseases , Heart Injuries , COVID-19/pathology , Cardiovascular Diseases/virology , Heart Injuries/virology , Humans
5.
J Nucl Med ; 62(11): 1631-1637, 2021 11.
Article in English | MEDLINE | ID: covidwho-1496930

ABSTRACT

In this study, we developed angiotensin-converting enzyme 2 (ACE2)-specific, peptide-derived 68Ga-labeled radiotracers, motivated by the hypotheses that ACE2 is an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and that modulation of ACE2 in coronavirus disease 2019 (COVID-19) drives severe organ injury. Methods: A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears 2 cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with 68Ga to generate peptide radiotracers (68Ga-NOTA-PEP). The aminocaproate-derived radiotracer 68Ga-NOTA-PEP4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model. Results: Cyclic DX-600-derived peptides had markedly lower half-maximal inhibitory concentrations than their linear counterparts. The 3 cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated half-maximal inhibitory concentrations similar to or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga, and the biodistribution of 68Ga-NOTA-PEP4 was determined in an hACE2 transgenic murine cohort. Pharmacologic concentrations of coadministered NOTA-PEP (blocking) showed a significant reduction of 68Ga-NOTA-PEP4 signals in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to in vivo results. Conclusion: NOTA-conjugated cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer, 68Ga-NOTA-PEP4, showed specific binding in the heart, liver, lungs and intestine-organs known to be affected in SARS-CoV-2 infection. These results suggest that 68Ga-NOTA-PEP4 could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2-infected murine models and COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2 , Gallium Radioisotopes/chemistry , Peptides, Cyclic , Animals , Male , Mice , Positron-Emission Tomography , Tissue Distribution
6.
J Med Virol ; 93(10): 5908-5916, 2021 10.
Article in English | MEDLINE | ID: covidwho-1432424

ABSTRACT

The main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 interactions with ACE2 may increase ectodomain shedding but consequences for the renin-angiotensin system and pathology in Coronavirus disease 2019 (COVID-19) remain unclear. We measured soluble ACE2 (sACE2) and sACE levels by enzyme-linked immunosorbent assay in 114 hospital-treated COVID-19 patients compared with 10 healthy controls; follow-up samples after four months were analyzed for 58 patients. Associations between sACE2 respectively sACE and risk factors for severe COVID-19, outcome, and inflammatory markers were investigated. Levels of sACE2 were higher in COVID-19 patients than in healthy controls, median 5.0 (interquartile range 2.8-11.8) ng/ml versus 1.4 (1.1-1.6) ng/ml, p < .0001. sACE2 was higher in men than women but was not affected by other risk factors for severe COVID-19. sACE2 decreased to 2.3 (1.6-3.9) ng/ml at follow-up, p < .0001, but remained higher than in healthy controls, p = .012. sACE was marginally lower during COVID-19 compared with at follow-up, 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p = .008. Levels of sACE2 and sACE did not differ depending on survival or disease severity. sACE2 during COVID-19 correlated with von Willebrand factor, factor VIII and D-dimer, while sACE correlated with interleukin 6, tumor necrosis factor α, and plasminogen activator inhibitor 1. Conclusions: sACE2 was transiently elevated in COVID-19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID-19 differed in correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Adult , Aged , Biomarkers/blood , Female , Follow-Up Studies , Humans , Inflammation , Male , Middle Aged , Peptidyl-Dipeptidase A/blood , Renin-Angiotensin System , Risk Factors , SARS-CoV-2
7.
Cytokine ; 140: 155430, 2021 04.
Article in English | MEDLINE | ID: covidwho-1385381

ABSTRACT

In vitro interferon (IFN)α treatment of primary human upper airway basal cells has been shown to drive ACE2 expression, the receptor of SARS-CoV-2. The protease furin is also involved in mediating SARS-CoV-2 and other viral infections, although its association with early IFN response has not been evaluated yet. In order to assess the in vivo relationship between ACE2 and furin expression and the IFN response in nasopharyngeal cells, we first examined ACE2 and furin levels and their correlation with the well-known marker of IFNs' activation, ISG15, in children (n = 59) and adults (n = 48), during respiratory diseases not caused by SARS-CoV-2. A strong positive correlation was found between ACE2 expression, but not of furin, and ISG15 in all patients analyzed. In addition, type I and III IFN stimulation experiments were performed to examine the IFN-mediated activation of ACE2 isoforms (full-length and truncated) and furin in epithelial cell lines. Following all the IFNs treatments, only the truncated ACE2 levels, were upregulated significantly in the A549 and Calu3 cells, in particular by type I IFNs. If confirmed in vivo following IFNs' activation, the induction of the truncated ACE2 isoform only would not enhance the risk of SARS-CoV-2 infection in the respiratory tract.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/prevention & control , Epithelial Cells/drug effects , Gene Expression/drug effects , Interferons/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adult , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/virology , Cell Line, Tumor , Child , Cytokines/genetics , Epithelial Cells/metabolism , Humans , Interferons/metabolism , Lung/cytology , Middle Aged , SARS-CoV-2/physiology , Ubiquitins/genetics
8.
Front Mol Biosci ; 7: 568954, 2020.
Article in English | MEDLINE | ID: covidwho-1389212

ABSTRACT

Because ACE2 is a host cell receptor of the SARS-CoV-2, an investigation of ACE2 expression in normal and virus-infected human tissues is crucial for understanding the mechanism of SARS-CoV-2 infection. We identified pathways associated with ACE2 expression and gene co-expression networks of ACE2 in pan-tissue based on the gene expression profiles in normal human tissues. We found that the pathways significantly associated with ACE2 upregulation were mainly involved in immune, stromal signature, metabolism, cell growth and proliferation, and cancer and other diseases. The number of genes having a significant positive expression correlation with ACE2 in females far exceeded that in males. The estrogen receptors (ESR1 and ESR2) and androgen receptor (AR) genes had a significant positive expression correlation with ACE2. Meanwhile, the enrichment levels of immune cells were positively associated with the expression levels of ESR1 and ESR2, while they were inversely associated with the expression levels of AR in pan-tissue and multiple individual tissues. It suggests that females are likely to have a more robust immune defense system against SARS-CoV-2 than males. ACE2 was upregulated in SARS-CoV-2-infected tissues relative to normal tissues and in SARS-CoV-2-infected males relative to females, while its expression levels had no significant difference between healthy females and males. Numerous immune-related pathways were highly enriched in SARS-CoV-2-infected males relative to females. These data indicate that males are more susceptible and more likely to have an excessive immune response to SARS-CoV-2 infection than females. This study furnishes potentially cues explaining why females have better clinical outcomes of SARS-CoV-2 infections than males and warrant further investigation for understanding the mechanism of SARS-CoV-2 infection.

9.
Front Immunol ; 11: 607314, 2020.
Article in English | MEDLINE | ID: covidwho-1389171

ABSTRACT

Acute lung injury (ALI) is an important cause of morbidity and mortality after viral infections, including influenza A virus H1N1, SARS-CoV, MERS-CoV, and SARS-CoV-2. The angiotensin I converting enzyme 2 (ACE2) is a key host membrane-bound protein that modulates ALI induced by viral infection, pulmonary acid aspiration, and sepsis. However, the contributions of ACE2 sequence variants to individual differences in disease risk and severity after viral infection are not understood. In this study, we quantified H1N1 influenza-infected lung transcriptomes across a family of 41 BXD recombinant inbred strains of mice and both parents-C57BL/6J and DBA/2J. In response to infection Ace2 mRNA levels decreased significantly for both parental strains and the expression levels was associated with disease severity (body weight loss) and viral load (expression levels of viral NA segment) across the BXD family members. Pulmonary RNA-seq for 43 lines was analyzed using weighted gene co-expression network analysis (WGCNA) and Bayesian network approaches. Ace2 not only participated in virus-induced ALI by interacting with TNF, MAPK, and NOTCH signaling pathways, but was also linked with high confidence to gene products that have important functions in the pulmonary epithelium, including Rnf128, Muc5b, and Tmprss2. Comparable sets of transcripts were also highlighted in parallel studies of human SARS-CoV-infected primary human airway epithelial cells. Using conventional mapping methods, we determined that weight loss at two and three days after viral infection maps to chromosome X-the location of Ace2. This finding motivated the hierarchical Bayesian network analysis, which defined molecular endophenotypes of lung infection linked to Ace2 expression and to a key disease outcome. Core members of this Bayesian network include Ace2, Atf4, Csf2, Cxcl2, Lif, Maml3, Muc5b, Reg3g, Ripk3, and Traf3. Collectively, these findings define a causally-rooted Ace2 modulatory network relevant to host response to viral infection and identify potential therapeutic targets for virus-induced respiratory diseases, including those caused by influenza and coronaviruses.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Lung/virology , Virus Diseases/genetics , Animals , Bayes Theorem , Epithelial Cells/virology , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Respiratory Mucosa/virology , Signal Transduction/genetics
10.
Cell Host Microbe ; 28(6): 867-879.e5, 2020 12 09.
Article in English | MEDLINE | ID: covidwho-1385264

ABSTRACT

The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we determined cryo-electron microscopy structures-at serological and endosomal pH-delineating spike recognition of up to three ACE2 molecules. RBDs freely adopted "up" conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Pandemics , Spike Glycoprotein, Coronavirus/ultrastructure , Amino Acid Sequence/genetics , Angiotensin-Converting Enzyme 2/ultrastructure , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19/pathology , COVID-19/virology , Cryoelectron Microscopy , Endosomes/ultrastructure , Humans , Hydrogen-Ion Concentration , Protein Binding , Protein Domains , Receptors, Virus/genetics , Receptors, Virus/ultrastructure , SARS-CoV-2/genetics , SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/genetics
11.
Am J Ther ; 28(3): e358-e360, 2020 Aug 03.
Article in English | MEDLINE | ID: covidwho-1349825

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly expanding global health crisis. A disintegrin and metalloproteinase 17 (ADAM17), an ectodomain sheddase, is a key component of ACE2 modulation and plays a complex role in inflammation and immunosurveillance. AREAS OF UNCERTAINTY: Much remains unknown regarding the immunopathogenesis of COVID-19, including how the virus affects ADAM17 expression, activity, and regulation. SEARCH STRATEGY: Three electronic databases (MEDLINE through PubMed, Embase through Ovid, and Google Scholar) were searched to identify articles relevant to ADAM17 and severe acute respiratory syndrome coronavirus 1 and 2. Relevant articles published from January 1, 2005, to April 30, 2020, were selected, and reference lists were screened and cross-referenced. We also searched preprint studies on medRxiv and bioRxiv given the rapidly evolving data on COVID-19 SARS-CoV-2. THERAPEUTIC OPINION: Infection with SARS-CoV-2 may lead to an increase in ADAM17 sheddase activity contributing to an exuberant macrophage-predominant inflammatory response and diminished immunosurveillance capacity for viral clearance. Emerging data suggest severe lung injury in COVID-19 is associated with higher levels of TNF-α and IL-6, T-cell lymphopenia and exhaustion, hypercoagulability, and a macrophage-predominant immune response. This clinical picture is consistent with dysregulation of many of the molecular pathways in which ADAM17 participates. CONCLUSIONS: Elucidation of the role of ADAM17 in COVID-19 may identify novel molecular targets for drug development and therapeutic repurposement.


Subject(s)
ADAM17 Protein , COVID-19 , SARS-CoV-2/physiology , Signal Transduction/immunology , ADAM17 Protein/immunology , ADAM17 Protein/metabolism , COVID-19/immunology , COVID-19/virology , Drug Discovery , Gene Expression , Humans , Immunity
12.
J Cell Physiol ; 236(10): 7045-7057, 2021 10.
Article in English | MEDLINE | ID: covidwho-1342890

ABSTRACT

The evolution of the SARS-CoV-2 new variants reported to be 70% more contagious than the earlier one is now spreading fast worldwide. There is an instant need to discover how the new variants interact with the host receptor (ACE2). Among the reported mutations in the Spike glycoprotein of the new variants, three are specific to the receptor-binding domain (RBD) and required insightful scrutiny for new therapeutic options. These structural evolutions in the RBD domain may impart a critical role to the unique pathogenicity of the SARS-CoV-2 new variants. Herein, using structural and biophysical approaches, we explored that the specific mutations in the UK (N501Y), South African (K417N-E484K-N501Y), Brazilian (K417T-E484K-N501Y), and hypothetical (N501Y-E484K) variants alter the binding affinity, create new inter-protein contacts and changes the internal structural dynamics thereby increases the binding and eventually the infectivity. Our investigation highlighted that the South African (K417N-E484K-N501Y), Brazilian (K417T-E484K-N501Y) variants are more lethal than the UK variant (N501Y). The behavior of the wild type and N501Y is comparable. Free energy calculations further confirmed that increased binding of the spike RBD to the ACE2 is mainly due to the electrostatic contribution. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection-driven epistasis in protein evolution. The triple mutants (South African and Brazilian) may pose a serious threat to the efficacy of the already developed vaccine. Our analysis would help to understand the binding and structural dynamics of the new mutations in the RBD domain of the Spike protein and demand further investigation in in vitro and in vivo models to design potential therapeutics against the new variants.


Subject(s)
Mutation/genetics , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Brazil , COVID-19/metabolism , Humans , Protein Binding/genetics , South Africa , United Kingdom , Virulence/genetics
13.
Elife ; 92020 04 27.
Article in English | MEDLINE | ID: covidwho-1344522

ABSTRACT

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.


The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs' cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Drug Development , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Angioedema/drug therapy , Angioedema/metabolism , Angioedema/pathology , Anti-Inflammatory Agents/therapeutic use , Betacoronavirus/physiology , Bradykinin Receptor Antagonists/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Kallikreins/metabolism , Kinins/metabolism , Lung/metabolism , Lung/pathology , Pandemics , Pneumonia, Viral/metabolism , Receptor, Bradykinin B1/metabolism , Receptor, Bradykinin B2/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2 , Signal Transduction
14.
Chin J Integr Med ; 26(7): 527-532, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1343028

ABSTRACT

OBJECTIVE: To seek potential Chinese herbal medicine (CHM) for the treatment of coronavirus disease 2019 (COVID-19) through the molecular docking of the medicine with SARS-CoV-2 3CL hydrolytic enzyme and the angiotensin converting enzyme II(ACE2) as receptors, using computer virtual screening technique, so as to provide a basis for combination forecasting. METHODS: The molecular docking of CHM with the SARS-Cov-2 3CL hydrolase and the ACE2 converting enzyme, which were taken as the targets, was achieved by the Autodock Vina software. The CHM monomers acting on 3CLpro and ACE2 receptors were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the active ingredients were selected, and the key CHMs and compounds were speculated. Based on the perspective of network pharmacology, the chemical-target network was constructed, and the functional enrichment analysis of gene ontology and the pathway enrichment analysis of Kyoto encyclopedia of genes and genomes were carried out by DAVID to speculate about the mechanism of action of the core drug pairs. RESULTS: There are 6 small molecule compounds that have the optimal binding energy with the two target proteins. Among 238 potential anti-COVID-19 herbs screened in total, 16 kinds of CHM containing the most active ingredients, and 5 candidate anti-COVID-19 herbs that had been used in high frequency, as well as a core drug pair, namely, Forsythiae Fructus-Lonicerae Japonicae Flos were selected. CONCLUSION: The core drug pair of Forsythiae Fructus-Lonicerae Japonicae Flos containing multiple components and targets is easy to combine with 3CLpro and ACE2, and exerts an anti-COVID-19 pneumonia effect through multi-component and multi-target, and plays the role of anti-COVID-19 pneumonia in multi-pathway.


Subject(s)
Betacoronavirus/metabolism , Computer Simulation , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/therapeutic use , Molecular Docking Simulation , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , COVID-19 , Gene Ontology , Humans , Pandemics , SARS-CoV-2 , Thermodynamics
15.
Respir Res ; 21(1): 154, 2020 Jun 18.
Article in English | MEDLINE | ID: covidwho-1331943

ABSTRACT

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.


Subject(s)
Coronavirus Infections/epidemiology , Electronic Nicotine Delivery Systems , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia/metabolism , Vaping/adverse effects , alpha7 Nicotinic Acetylcholine Receptor/genetics , Angiotensin-Converting Enzyme 2 , Animals , Blood Gas Analysis , Blotting, Western , Bronchoalveolar Lavage Fluid , COVID-19 , Cytokines/analysis , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pandemics , Pneumonia/physiopathology , Random Allocation , Reference Values , Role , Severe Acute Respiratory Syndrome/epidemiology , Signal Transduction/genetics
16.
J Periodontol ; 92(7): 35-43, 2021 07.
Article in English | MEDLINE | ID: covidwho-1326784

ABSTRACT

BACKGROUND: Type 2 diabetes and periodontitis predispose to a higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recent studies show upregulation of innate immuno-regulatory microRNA-146a and -155 in oral fluids of patients with type 2 diabetes as well as of patients with periodontitis. The aim was to investigate whether upregulation of these microRNAs may relate to patient susceptibility to the infection via modulation of SARS-CoV-2 cellular entry factors expression. METHODS: Due to limited experimental feasibility and health risks in Coronavirus Disease 2019, bioinformatic analyses combining with system biology were used as initial investigation of interaction between microRNA-146 and -155 and genes encoding SARS-CoV-2 entry factors. RESULTS: SARS-CoV-2 cellular entry factors are expressed in salivary glands and masticatory mucosa (tongue) at different expression levels, comparable with those measured in lungs and tonsil. MicroRNA-146 and -155 are widely involved in the regulation of SARS-CoV-2 oral cellular entry factors and may enhance expression of ACE2 and modulate genes involved in host immunity. CONCLUSIONS: Diabetes- and periodontitis-induced increase in microRNA-146a and -155 in oral cavity is predicted to upregulate angiotensin-converting enzyme 2 expression, essential SARS-CoV-2 entry receptors, and modulate host antiviral response. As it could suggest increased infectivity of diabetes and periodontitis patients, additional protective measures for periodontists are recommended.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , MicroRNAs , Periodontitis , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Humans , MicroRNAs/genetics , Periodontitis/genetics , SARS-CoV-2
18.
Med Hypotheses ; 153: 110627, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1275586

ABSTRACT

Different mechanisms forwarded to understand anosmia and ageusia in coronavirus patients are not adequate to explain reversible anosmia and ageusia, which are resolved quickly. In addition, the reason behind the impaired chemesthetic sensations in some coronavirus patients remains unknown. In the present paper it is proposed that SARS-CoV-2 patients suffer from depletion of tryptophan, as ACE2, a key element in the process of absorption of tryptophan from the food, is significantly reduced in the patients as coronavirus uses ACE2 as the receptor to enter the host cells. The tryptophan depletion leads to a deficit of serotonin (5-HT) in SARS-COV-2 patients because tryptophan is the precursor in the synthesis of 5-HT. Such 5-HT deficiency can explain anosmia, ageusia and dysfunctional chemesthesis in COVID-19, given the fact that 5-HT is an important neuromodulator in the olfactory neurons, taste receptor cells and transient receptor potential channels (TRP channels) involved in chemesthesis. In addition, 5-HT deficiency worsens silent hypoxemia and depresses hypoxic pulmonary vasoconstriction leading to increased severity of the disease. Also, the levels of anti-inflammatory melatonin (synthesized from 5-HT) and nicotinamide adenine dinucleotide (NAD+, produced from niacin whose precursor is the tryptophan) might decrease in coronavirus patients resulting in the aggravation of the disease. Interestingly, selective serotonin reuptake inhibitors (SSRIs) may not be of much help in correcting the 5-HT deficiency in COVID-19 patients, as their efficacy goes down significantly when there is depletion of tryptophan in the system. Hence, tryptophan supplementation may herald a radical change in the treatment of COVID-19 and accordingly, clinical trials (therapeutic / prophylactic) should be conducted on coronavirus patients to find out how tryptophan supplementation (oral or parenteral, the latter in severe cases where there is hardly any absorption of tryptophan from the food) helps in curing, relieving or preventing the olfactory, gustatory and chemesthetic dysfunctions and in lessening the severity of the disease.


Subject(s)
Ageusia , COVID-19 , Olfaction Disorders , Anosmia , Humans , SARS-CoV-2 , Serotonin
19.
J Autoimmun ; 122: 102683, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267726

ABSTRACT

The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; rPearson = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Autoantibodies/blood , Autoantigens/immunology , COVID-19/immunology , Receptor, Angiotensin, Type 1/immunology , Aged , Autoantibodies/immunology , COVID-19/blood , Female , Humans , Male , Middle Aged , Renin-Angiotensin System/immunology , SARS-CoV-2
20.
Arthritis Res Ther ; 23(1): 166, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1266501

ABSTRACT

BACKGROUND: To investigate whether methotrexate treatment may affect the susceptibility to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Clinical assessment of symptoms, SARS-CoV-2 RNA, and anti-SARS-CoV-2 IgG in an initial case series of four families and confirmatory case series of seven families, within which one family member developed coronavirus disease 19 (COVID-19) and exposed another family member receiving methotrexate treatment; experimental part with methotrexate treatment of mice and organoids followed by the assessment of mRNA and protein expression of the SARS-CoV-2 receptor angiotensin-converting enzyme (ACE)-2. RESULTS: In the initial case series, three of four women on a joint ski trip developed COVID-19, while the fourth woman, under treatment with methotrexate, remained virus-free. Two of the three diseased women infected their husbands, while the third husband treated with methotrexate remained virus-free. In addition, 7 other families were identified in a follow-up case series, in which one member developed COVID-19, while the other, receiving methotrexate, remained healthy. Experimentally, when mice were treated with methotrexate, ACE2 expression significantly decreased in the lung, in the intestinal epithelium, and in intestinal organoids. CONCLUSION: These clinical and experimental data indicate that methotrexate has certain protective effects on SARS-CoV-2 infection via downregulating ACE2.


Subject(s)
COVID-19 , Animals , Humans , Methotrexate , Mice , RNA, Viral , SARS-CoV-2
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