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1.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1214016

ABSTRACT

Here, we present a physiologically relevant model of the human pulmonary alveoli. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung.


Subject(s)
Lab-On-A-Chip Devices , Models, Biological , Pulmonary Alveoli/physiology , Alveolar Epithelial Cells , Antiviral Agents/pharmacology , Cigarette Smoking/adverse effects , Dimethylpolysiloxanes/chemistry , Gelatin/chemistry , Humans , Hydrogels/chemistry , Methacrylates/chemistry , Porosity , Pulmonary Alveoli/cytology , Pulmonary Alveoli/pathology , Respiration , Respiratory Mucosa/cytology , Respiratory Mucosa/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
2.
Pathogens ; 10(5)2021 Apr 23.
Article in English | MEDLINE | ID: covidwho-1201175

ABSTRACT

The SARS-CoV-2 pandemic has inspired renewed interest in understanding the fundamental pathology of acute respiratory distress syndrome (ARDS) following infection. However, the pathogenesis of ARDS following SRAS-CoV-2 infection remains largely unknown. In the present study, we examined apoptosis in postmortem lung sections from COVID-19 patients and in lung tissues from a non-human primate model of SARS-CoV-2 infection, in a cell-type manner, including type 1 and 2 alveolar cells and vascular endothelial cells (ECs), macrophages, and T cells. Multiple-target immunofluorescence assays and Western blotting suggest both intrinsic and extrinsic apoptotic pathways are activated during SARS-CoV-2 infection. Furthermore, we observed that SARS-CoV-2 fails to induce apoptosis in human bronchial epithelial cells (i.e., BEAS2B cells) and primary human umbilical vein endothelial cells (HUVECs), which are refractory to SARS-CoV-2 infection. However, infection of co-cultured Vero cells and HUVECs or Vero cells and BEAS2B cells with SARS-CoV-2 induced apoptosis in both Vero cells and HUVECs/BEAS2B cells but did not alter the permissiveness of HUVECs or BEAS2B cells to the virus. Post-exposure treatment of the co-culture of Vero cells and HUVECs with a novel non-cyclic nucleotide small molecule EPAC1-specific activator reduced apoptosis in HUVECs. These findings may help to delineate a novel insight into the pathogenesis of ARDS following SARS-CoV-2 infection.

3.
ERJ Open Res ; 7(2)2021 Apr.
Article in English | MEDLINE | ID: covidwho-1183500

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has a variable degree of severity according to underlying comorbidities and life-style. Several research groups have reported an association between cigarette smoking and increased severity of COVID-19. The exact mechanism of action is largely unclear. We exposed low angiotensin-converting enzyme 2 (ACE2)-expressing human pulmonary adenocarcinoma A549 epithelial cells to nicotine and assessed ACE2 expression at different times. We further used the nicotine-exposed cells in a virus neutralisation assay. Nicotine exposure induces rapid and long-lasting increases in gene and protein expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2, which in turn translates into increased competence for SARS-CoV-2 replication and cytopathic effect. These findings show that nicotine worsens SARS-CoV-2 pulmonary infection and have implications for public health policies.

4.
J Inflamm Res ; 14: 869-884, 2021.
Article in English | MEDLINE | ID: covidwho-1138640

ABSTRACT

PURPOSE: Coronil is a tri-herbal formulation containing extracts from Withania somnifera, Tinospora cordifolia, and Ocimum sanctum. Recently, it was shown that Coronil rescued humanized zebrafish from SARS-CoV-2 induced pathologies. Based on reported computational studies on the phytochemicals present in Coronil, it could be a potential inhibitor of SARS-CoV-2 entry into the host cell and associated cytokines' production. METHODS: Through an ELISA-based biochemical assay, effects of Coronil on interaction between ACE-2 and different mutants of viral spike (S) protein, crucial for viral invasion of host cell, were evaluated. Additionally, using recombinant pseudoviruses having SARS-CoV-2 spike (S) protein in their envelopes and firefly luciferase reporter in their genomes, effects of Coronil on virus entry into human alveolar epithelial cells were evaluated through luciferase assay. UHPLC profiled Coronil also modulated S-protein mediated production of pro-inflammatory cytokines in A549 cells, like interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α), as evaluated through RT-qPCR and ELISA. RESULTS: Coronil effectively inhibited the interaction of ACE-2 not only with the wild-type S protein (SWT) but also with its currently prevalent and more infectious variant (SD614G) and another mutant (SW436R) with significantly higher affinity toward ACE-2. Treatment with Coronil significantly reduced the increased levels of IL-6, IL-1ß, and TNF-α in A549 cells incubated with different S-protein variants in a dose-dependent manner. Likewise, it also prevented the SARS-CoV-2 S-protein pseudotyped vesicular stomatitis virus (VSVppSARS-2S) mediated cytokine response in these cells by reducing entry of pseudoviruses into host cells. CONCLUSION: Coronil prevented SARS-CoV-2 S-protein mediated viral entry into A549 cells by inhibiting spike protein-ACE-2 interactions. SARS-CoV-2 S protein induced inflammatory cytokine response in these cells was also moderated by Coronil.

5.
Cell ; 184(1): 92-105.e16, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064907

ABSTRACT

To better understand host-virus genetic dependencies and find potential therapeutic targets for COVID-19, we performed a genome-scale CRISPR loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection of human alveolar epithelial cells. Top-ranked genes cluster into distinct pathways, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. We validate these gene targets using several orthogonal methods such as CRISPR knockout, RNA interference knockdown, and small-molecule inhibitors. Using single-cell RNA-sequencing, we identify shared transcriptional changes in cholesterol biosynthesis upon loss of top-ranked genes. In addition, given the key role of the ACE2 receptor in the early stages of viral entry, we show that loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells. Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.


Subject(s)
COVID-19/genetics , COVID-19/virology , Host-Pathogen Interactions , SARS-CoV-2/physiology , A549 Cells , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/metabolism , Biosynthetic Pathways , COVID-19/metabolism , Cholesterol/biosynthesis , Clustered Regularly Interspaced Short Palindromic Repeats , Endosomes/metabolism , Gene Expression Profiling , Gene Knockdown Techniques , Gene Knockout Techniques/methods , Genome-Wide Association Study , Host-Pathogen Interactions/drug effects , Humans , RNA Interference , SARS-CoV-2/growth & development , Single-Cell Analysis , Viral Load/drug effects , rab GTP-Binding Proteins/genetics
6.
Aging Dis ; 12(1): 42-49, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1060948

ABSTRACT

COVID-19 is prevalent in the elderly. Old individuals are more likely to develop pneumonia and respiratory failure due to alveolar damage, suggesting that lung senescence may increase the susceptibility to SARS-CoV-2 infection and replication. Considering that human coronavirus (HCoVs; SARS-CoV-2 and SARS-CoV) require host cellular factors for infection and replication, we analyzed Genotype-Tissue Expression (GTEx) data to test whether lung aging is associated with transcriptional changes in human protein-coding genes that potentially interact with these viruses. We found decreased expression of the gene tribbles homolog 3 (TRIB3) during aging in male individuals, and its protein was predicted to interact with HCoVs nucleocapsid protein and RNA-dependent RNA polymerase. Using publicly available lung single-cell data, we found TRIB3 expressed mainly in alveolar epithelial cells that express SARS-CoV-2 receptor ACE2. Functional enrichment analysis of age-related genes, in common with SARS-CoV-induced perturbations, revealed genes associated with the mitotic cell cycle and surfactant metabolism. Given that TRIB3 was previously reported to decrease virus infection and replication, the decreased expression of TRIB3 in aged lungs may help explain why older male patients are related to more severe cases of the COVID-19. Thus, drugs that stimulate TRIB3 expression should be evaluated as a potential therapy for the disease.

7.
Am J Respir Cell Mol Biol ; 64(1): 79-88, 2021 01.
Article in English | MEDLINE | ID: covidwho-1004249

ABSTRACT

Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus-host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6) mice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2). Mice were infected with SARS-CoV-2 at Day 4 after transduction and developed interstitial pneumonia associated with perivascular inflammation, accompanied by significantly higher viral load in lungs at Days 3, 6, and 12 after infection compared with Ad5-empty control group. SARS-CoV-2 was detected in pneumocytes in alveolar septa. Transcriptomic analysis of lungs demonstrated that the infected Ad5-hACE mice had a significant increase in IFN-dependent chemokines Cxcl9 and Cxcl10, and genes associated with effector T-cell populations including Cd3 g, Cd8a, and Gzmb. Pathway analysis showed that several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the data set, including cytokine-cytokine receptor interaction, the chemokine signaling pathway, the NOD-like receptor signaling pathway, the measles pathway, and the IL-17 signaling pathway. This response is correlative to clinical response in lungs of patients with COVID-19. These results demonstrate that expression of hACE2 via adenovirus delivery system sensitized the mouse to SARS-CoV-2 infection and resulted in the development of a mild COVID-19 phenotype, highlighting the immune and inflammatory host responses to SARS-CoV-2 infection. This rapidly deployable COVID-19 mouse model is useful for preclinical and pathogenesis studies of COVID-19.


Subject(s)
Alveolar Epithelial Cells/immunology , COVID-19/immunology , Gene Expression , SARS-CoV-2/immunology , Signal Transduction/immunology , Adenoviridae/genetics , Adenoviridae/metabolism , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/biosynthesis , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/genetics , COVID-19/metabolism , COVID-19/pathology , Cytokines/genetics , Cytokines/immunology , Disease Models, Animal , Humans , Mice , Mice, Transgenic , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Signal Transduction/genetics , Transduction, Genetic
8.
Cell Death Dis ; 11(12): 1042, 2020 12 08.
Article in English | MEDLINE | ID: covidwho-969908

ABSTRACT

COVID-19, caused by SARS-CoV-2, is an acute and rapidly developing pandemic, which leads to a global health crisis. SARS-CoV-2 primarily attacks human alveoli and causes severe lung infection and damage. To better understand the molecular basis of this disease, we sought to characterize the responses of alveolar epithelium and its adjacent microvascular endothelium to viral infection under a co-culture system. SARS-CoV-2 infection caused massive virus replication and dramatic organelles remodeling in alveolar epithelial cells, alone. While, viral infection affected endothelial cells in an indirect manner, which was mediated by infected alveolar epithelium. Proteomics analysis and TEM examinations showed viral infection caused global proteomic modulations and marked ultrastructural changes in both epithelial cells and endothelial cells under the co-culture system. In particular, viral infection elicited global protein changes and structural reorganizations across many sub-cellular compartments in epithelial cells. Among the affected organelles, mitochondrion seems to be a primary target organelle. Besides, according to EM and proteomic results, we identified Daurisoline, a potent autophagy inhibitor, could inhibit virus replication effectively in host cells. Collectively, our study revealed an unrecognized cross-talk between epithelium and endothelium, which contributed to alveolar-capillary injury during SARS-CoV-2 infection. These new findings will expand our understanding of COVID-19 and may also be helpful for targeted drug development.


Subject(s)
COVID-19/pathology , Cell Communication/physiology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Cell Line , Coculture Techniques , Down-Regulation , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelial Cells/virology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Microscopy, Electron, Transmission , Mitochondria/pathology , Mitochondria/virology , Proteome/metabolism , Proteomics/methods , Pulmonary Alveoli/cytology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism , Up-Regulation
9.
Zhonghua Wai Ke Za Zhi ; 58(4): 273-277, 2020 Apr 01.
Article in Chinese | MEDLINE | ID: covidwho-824073

ABSTRACT

In this paper, the mechanism of destroying human alveolar epithelial cells and pulmonary tissue by 2019 novel coronavirus (2019-nCoV) was discussed firstly. There may be multiple mechanisms including killing directly the target cells and hyperinflammatory responses. Secondly, the clinical features, CT imaging, short-term and long-term pulmonary function damage of the 2019 coronavirus disease (COVID-19) was analyzed. Finally, some suggestions for thoracic surgery clinical practice in non-epidemic area during and after the epidemic of COVID-19 were provided, to help all the thoracic surgery patients receive active and effective treatment.


Subject(s)
Alveolar Epithelial Cells/virology , Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Thoracic Surgery , Alveolar Epithelial Cells/pathology , COVID-19 , Humans , Lung/pathology , Lung/virology , Pandemics , SARS-CoV-2
10.
Adv Mater ; 32(43): e2004901, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-756243

ABSTRACT

The COVID-19 pandemic has taken a significant toll on people worldwide, and there are currently no specific antivirus drugs or vaccines. Herein it is a therapeutic based on catalase, an antioxidant enzyme that can effectively breakdown hydrogen peroxide and minimize the downstream reactive oxygen species, which are excessively produced resulting from the infection and inflammatory process, is reported. Catalase assists to regulate production of cytokines, protect oxidative injury, and repress replication of SARS-CoV-2, as demonstrated in human leukocytes and alveolar epithelial cells, and rhesus macaques, without noticeable toxicity. Such a therapeutic can be readily manufactured at low cost as a potential treatment for COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Betacoronavirus/drug effects , Catalase/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Anti-Inflammatory Agents/pharmacokinetics , Antioxidants/pharmacokinetics , Betacoronavirus/physiology , COVID-19 , Catalase/pharmacokinetics , Cell Line , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Leukocytes/drug effects , Leukocytes/metabolism , Leukocytes/virology , Macaca mulatta , Mice , Mice, Inbred BALB C , Oxidative Stress/drug effects , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/virology , SARS-CoV-2 , Virus Replication/drug effects
11.
Nature ; 586(7827): 113-119, 2020 10.
Article in English | MEDLINE | ID: covidwho-672174

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2-4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.


Subject(s)
Antiviral Agents/analysis , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Evaluation, Preclinical , Drug Repositioning , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/drug effects , Betacoronavirus/growth & development , COVID-19 , Cell Line , Cysteine Proteinase Inhibitors/analysis , Cysteine Proteinase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Gene Expression Regulation/drug effects , Humans , Hydrazones , Induced Pluripotent Stem Cells/cytology , Models, Biological , Morpholines/analysis , Morpholines/pharmacology , Pandemics , Pyrimidines , Reproducibility of Results , SARS-CoV-2 , Small Molecule Libraries/analysis , Small Molecule Libraries/pharmacology , Triazines/analysis , Triazines/pharmacology , Virus Internalization/drug effects , Virus Replication/drug effects
12.
Eur Respir J ; 56(5)2020 Nov.
Article in English | MEDLINE | ID: covidwho-648811

ABSTRACT

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection.Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model.Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection.


Subject(s)
Coronavirus Infections/prevention & control , Cyclophilins/antagonists & inhibitors , Cyclosporine/pharmacology , Interferons/metabolism , Middle East Respiratory Syndrome Coronavirus/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Animals , Calcineurin Inhibitors/pharmacology , Cell Culture Techniques , Coronavirus Infections/metabolism , Disease Models, Animal , Humans , Interferon Regulatory Factor-1/drug effects , Interferon Regulatory Factor-1/metabolism , Interferons/drug effects , Mice , Middle East Respiratory Syndrome Coronavirus/physiology , Virus Replication/drug effects
13.
Vacunas ; 21(1): 17-22, 2020.
Article in Spanish | MEDLINE | ID: covidwho-612430

ABSTRACT

On December 31, 2019, an outbreak of pneumonia of unknown etiology was detected in the city of Wuhan (China). A week later, a new coronavirus was isolated in these patients, initially designated as 2019-nCoV and subsequently SARS-CoV-2. This is a new virus that is much closer genetically to the coronavirus of bats than to human SARS. The new virus infects and replicates in the lung parenchyma pneumocytes and macrophages in which the ACE-2 cell receptor resides. He has now infected many more people than his predecessors (> 85,000). From the clinical point of view, those infected have an average age of 55 years; the main symptoms are fever, dry cough, lymphopenia, dyspnea, and pneumonia in its severe form. The overall lethality rate is 2-3% in China and 0.1% in cases detected outside of this country. The incubation period has been set at about 3 days (0-24 days). There are no specific antivirals or vaccines.

14.
Lancet Respir Med ; 8(7): 687-695, 2020 07.
Article in English | MEDLINE | ID: covidwho-197584

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis. METHODS: We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls. FINDINGS: SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV. INTERPRETATION: The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens. FUNDING: US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.


Subject(s)
Betacoronavirus/immunology , Conjunctiva/virology , Coronavirus Infections/immunology , Immunity, Innate/immunology , Pneumonia, Viral/immunology , Respiratory System/virology , Viral Tropism/physiology , Virus Replication/physiology , Adult , Aged , Aged, 80 and over , Betacoronavirus/physiology , COVID-19 , Conjunctiva/immunology , Conjunctiva/physiopathology , Coronavirus Infections/physiopathology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/physiopathology , Respiratory Mucosa/immunology , Respiratory Mucosa/physiopathology , Respiratory Mucosa/virology , Respiratory System/immunology , Respiratory System/physiopathology , SARS-CoV-2
15.
J Med Virol ; 92(7): 726-730, 2020 07.
Article in English | MEDLINE | ID: covidwho-17559

ABSTRACT

This article reviews the correlation between angiotensin-converting enzyme 2 (ACE2) and severe risk factors for coronavirus disease 2019 (COVID-19) and the possible mechanisms. ACE2 is a crucial component of the renin-angiotensin system (RAS). The classical RAS ACE-Ang II-AT1R regulatory axis and the ACE2-Ang 1-7-MasR counter-regulatory axis play an essential role in maintaining homeostasis in humans. ACE2 is widely distributed in the heart, kidneys, lungs, and testes. ACE2 antagonizes the activation of the classical RAS system and protects against organ damage, protecting against hypertension, diabetes, and cardiovascular disease. Similar to SARS-CoV, SARS-CoV-2 also uses the ACE2 receptor to invade human alveolar epithelial cells. Acute respiratory distress syndrome (ARDS) is a clinical high-mortality disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of patients with COVID-19 is related to factors such as sex (male), age (>60 years), underlying diseases (hypertension, diabetes, and cardiovascular disease), secondary ARDS, and other relevant factors. Because of these protective effects of ACE2 on chronic underlying diseases and ARDS, the development of spike protein-based vaccine and drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID-19 in the future.


Subject(s)
Betacoronavirus/pathogenicity , Cardiovascular Diseases/genetics , Coronavirus Infections/genetics , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics , Age Factors , Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Cardiovascular Diseases/complications , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Peptide Fragments/therapeutic use , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Prognosis , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Sex Factors , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism
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