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1.
Molecules ; 27(3)2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1674736

ABSTRACT

Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.


Subject(s)
Butyrates/pharmacology , COVID-19/drug therapy , SARS-CoV-2/metabolism , Antiviral Agents/pharmacology , Butyrates/metabolism , COVID-19/metabolism , Caco-2 Cells , Enterocytes/drug effects , Enterocytes/metabolism , Gene Expression/genetics , Gene Expression Regulation/genetics , Humans , Intestines/drug effects , Intestines/metabolism , Male , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
2.
Sci Rep ; 11(1): 21725, 2021 11 05.
Article in English | MEDLINE | ID: covidwho-1504567

ABSTRACT

SARS-CoV-2 enters the intestine by the spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptors in enterocyte apical membranes, leading to diarrhea in some patients. Early treatment of COVID-19-associated diarrhea could relieve symptoms and limit viral spread within the gastrointestinal (GI) tract. Diosmectite, an aluminomagnesium silicate adsorbent clay with antidiarrheal effects, is recommended in some COVID-19 management protocols. In rotavirus models, diosmectite prevents pathogenic effects by binding the virus and its enterotoxin. We tested the trapping and anti-inflammatory properties of diosmectite in a SARS-CoV-2 model. Trapping effects were tested in Caco-2 cells using spike protein receptor-binding domain (RBD) and heat-inactivated SARS-CoV-2 preparations. Trapping was assessed by immunofluorescence, alone or in the presence of cells. The effect of diosmectite on nuclear factor kappa B (NF-kappaB) activation and CXCL10 secretion induced by the spike protein RBD and heat-inactivated SARS-CoV-2 were analyzed by Western blot and ELISA, respectively. Diosmectite bound the spike protein RBD and SARS-CoV-2 preparation, and inhibited interaction of the spike protein RBD with ACE2 receptors on the Caco-2 cell surface. Diosmectite exposure also inhibited NF-kappaB activation and CXCL10 secretion. These data provide direct evidence that diosmectite can bind SARS-CoV-2 components and inhibit downstream inflammation, supporting a mechanistic rationale for consideration of diosmectite as a management option for COVID-19-associated diarrhea.


Subject(s)
COVID-19/drug therapy , Chemokine CXCL10/metabolism , NF-kappa B p50 Subunit/metabolism , SARS-CoV-2 , Silicates/chemistry , Adsorption , Aluminum Compounds/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents , Binding Sites , Caco-2 Cells , Chromatography, Liquid , Clay , Diarrhea/etiology , Diarrhea/therapy , Enterocytes/metabolism , Gastroenterology , Humans , Magnesium Compounds/chemistry , Mass Spectrometry , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding/drug effects , Protein Domains , Rotavirus , Silicates/metabolism
3.
Int J Mol Sci ; 22(19)2021 Sep 28.
Article in English | MEDLINE | ID: covidwho-1444228

ABSTRACT

For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 (ACE2), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase (DDC), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2, DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.


Subject(s)
Brain/pathology , COVID-19/complications , Gene Expression Regulation , Intestine, Small/pathology , Angiotensin-Converting Enzyme 2/genetics , Aromatic-L-Amino-Acid Decarboxylases/genetics , Brain/metabolism , COVID-19/genetics , COVID-19/pathology , Cells, Cultured , Enterocytes/metabolism , Enterocytes/pathology , Humans , Intestine, Small/metabolism , SARS-CoV-2/isolation & purification
4.
Commun Biol ; 4(1): 631, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1283664

ABSTRACT

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Subject(s)
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
5.
Mol Biol Rep ; 48(5): 4667-4675, 2021 May.
Article in English | MEDLINE | ID: covidwho-1237535

ABSTRACT

The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, metastasis and viral infections. Recent studies have shown that TMPRSS2 expressed on cell surface of host cells could play a crucial role in activation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein which facilitates the rapid early entry of the virus into host cells. In addition, direct suppression of TMPRSS2 using small drug inhibitors has been demonstrated to be effective in decreasing SARS-CoV-2 infection in vitro, which presents TMPRSS2 protease as a potential therapeutic strategy for SARS-CoV-2 infection. Recently, SARS-CoV-2 has been shown to be capable of infecting gastrointestinal enterocytes and to provoke gastrointestinal disorders in patients with COVID-19 disease, which is considered as a new transmission route and target organ of SARS-CoV-2. In this review, we highlight the biochemical properties of TMPRSS2 protease and discuss the potential targeting of TMPRSS2 by inhibitors to prevent the SARS-CoV-2 spreading through gastro-intestinal tract system as well as the hurdles that need to be overcome.


Subject(s)
COVID-19/metabolism , Enterocytes/drug effects , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Evaluation, Preclinical , Enterocytes/metabolism , Enterocytes/virology , Humans , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
6.
Infect Genet Evol ; 92: 104892, 2021 08.
Article in English | MEDLINE | ID: covidwho-1213429

ABSTRACT

Novel coronavirus SARS-CoV-2 was recently outbreak worldwide causes severe acute respiratory syndrome along with gastrointestinal symptoms for some infected patients. Information on detail pathogenesis, host immune responses and responsible biological pathways are limited. Therefore, infection specific host gut responses and dietary supplements to neutralize immune inflammation demand extensive research. This study aimed to find differences in global co-expression protein-protein interaction sub-network and enriched biological processes in SARS-CoV and SARS-CoV-2 infected gut enterocytes cell line. Attempts have also been made to predict some dietary supplements to boost human health. The SARS-CoV and SARS-CoV-2 infected differential express proteins were integrated with the human protein interaction network and co-expression subnetworks were constructed. Common hubs of these sub-networks reshape central cellular pathways of metabolic processes, lipid localization, hypoxia response to decrease oxygen level and transport of bio-molecules. The major biological process enriched in the unique hub of SARS-CoV-2 significantly differ from SARS-CoV, related to interferon signaling, regulation of viral process and influenza-A enzymatic pathway. Predicted dietary supplements can improve SARS-CoV-2 infected person''s health by boosting the host immunity/reducing inflammation. To the best of our knowledge this is the first report on co-expression network mediated biological process in human gut enterocytes to predict dietary supplements/compounds.


Subject(s)
COVID-19/virology , Enterocytes/metabolism , Enterocytes/virology , SARS Virus/metabolism , SARS-CoV-2/metabolism , Dietary Supplements , Gene Expression Regulation , Humans , Protein Interaction Maps , RNA-Seq , SARS Virus/genetics , SARS-CoV-2/genetics
7.
Biol Open ; 10(3)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1148236

ABSTRACT

People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with coronavirus SARS-CoV-2, which causes COVID-19. Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, counteracting its chronic effects, and serves as the SARS-CoV-2 receptor. Ace, the coronavirus, and COVID-19 comorbidities all regulate Ace2, but we do not yet understand how. To exploit zebrafish (Danio rerio) to help understand the relationship of the RAAS to COVID-19, we must identify zebrafish orthologs and co-orthologs of human RAAS genes and understand their expression patterns. To achieve these goals, we conducted genomic and phylogenetic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have one or more zebrafish orthologs or co-orthologs. Results identified a specific type of enterocyte as the specific site of expression of zebrafish orthologs of key RAAS components, including Ace, Ace2, Slc6a19 (SARS-CoV-2 co-receptor), and the Angiotensin-related peptide cleaving enzymes Anpep (receptor for the common cold coronavirus HCoV-229E), and Dpp4 (receptor for the Middle East Respiratory Syndrome virus, MERS-CoV). Results identified specific vascular cell subtypes expressing Ang II receptors, apelin, and apelin receptor genes. These results identify genes and cell types to exploit zebrafish as a disease model for understanding mechanisms of COVID-19.


Subject(s)
Enterocytes , Gene Expression Regulation , Renin-Angiotensin System/genetics , SARS-CoV-2 , Zebrafish Proteins , Zebrafish , Animals , COVID-19/genetics , COVID-19/metabolism , Disease Models, Animal , Enterocytes/metabolism , Enterocytes/virology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish/virology , Zebrafish Proteins/biosynthesis , Zebrafish Proteins/genetics
8.
EMBO Mol Med ; 13(4): e13191, 2021 04 09.
Article in English | MEDLINE | ID: covidwho-1068062

ABSTRACT

SARS-CoV-2, the agent that causes COVID-19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin-converting enzyme-2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance, but severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear the infection. Using primary epithelial organoids from human colon, we explored how the central antiviral mediator IFN-γ, which is elevated in COVID-19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS-CoV-2. In mouse and human colon, ACE2 is mainly expressed by surface enterocytes. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN-γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2, increased susceptibility to SARS-CoV-2 infection, and resulted in enhanced virus production in infected cells. Similarly, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We here reveal a mechanism by which IFN-γ-driven inflammatory responses induce a vulnerable epithelial state with robust replication of SARS-CoV-2, which may have an impact on disease outcome and virus transmission.


Subject(s)
COVID-19/etiology , Interferon-gamma/immunology , Models, Immunological , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/pathology , Cell Differentiation/immunology , Colon/immunology , Colon/pathology , Colon/virology , Disease Susceptibility , Enterocytes/metabolism , Enterocytes/pathology , Enterocytes/virology , Gene Expression , Host Microbial Interactions/immunology , Humans , Interferon-gamma/administration & dosage , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Intestinal Mucosa/virology , Mice , Organoids/immunology , Organoids/pathology , Organoids/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Virus Replication/immunology
9.
Cell Rep ; 32(12): 108175, 2020 09 22.
Article in English | MEDLINE | ID: covidwho-747293

ABSTRACT

To predict the tropism of human coronaviruses, we profile 28 SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) using single-cell transcriptomics across various healthy human tissues. SCARFs include cellular factors both facilitating and restricting viral entry. Intestinal goblet cells, enterocytes, and kidney proximal tubule cells appear highly permissive to SARS-CoV-2, consistent with clinical data. Our analysis also predicts non-canonical entry paths for lung and brain infections. Spermatogonial cells and prostate endocrine cells also appear to be permissive to SARS-CoV-2 infection, suggesting male-specific vulnerabilities. Both pro- and anti-viral factors are highly expressed within the nasal epithelium, with potential age-dependent variation, predicting an important battleground for coronavirus infection. Our analysis also suggests that early embryonic and placental development are at moderate risk of infection. Lastly, SCARF expression appears broadly conserved across a subset of primate organs examined. Our study establishes a resource for investigations of coronavirus biology and pathology.


Subject(s)
Coronavirus Infections/pathology , Nasal Mucosa/metabolism , Pneumonia, Viral/pathology , Receptors, Virus/genetics , Viral Tropism/genetics , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/growth & development , COVID-19 , Cell Line , Chlorocebus aethiops , Enterocytes/metabolism , Gene Expression Profiling , Goblet Cells/metabolism , HEK293 Cells , Humans , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/metabolism , Nasal Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis , Vero Cells
11.
Int J Biol Sci ; 16(13): 2464-2476, 2020.
Article in English | MEDLINE | ID: covidwho-695855

ABSTRACT

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused infections worldwide. However, the correlation between the immune infiltration and coronavirus disease 2019 (COVID-19) susceptibility or severity in cancer patients remains to be fully elucidated. ACE2 expressions in normal tissues, cancers and cell lines were comprehensively assessed. Furthermore, we compared ACE2 expression between cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we performed gene set enrichment analysis (GSEA) to investigate the related signaling pathways. Finally, the correlations between ACE2 expression and immune infiltration were investigated via Tumor Immune Estimation Resource (TIMER) and GEPIA. We found that ACE2 was predominantly expressed in both adult and fetal tissues from the digestive, urinary and male reproductive tracts; moreover, ACE2 expressions in corresponding cancers were generally higher than that in matched healthy tissues. GSEA showed that various metabolic and immune-related pathways were significantly associated with ACE2 expression across multiple cancer types. Intriguingly, we found that ACE2 expression correlated significantly with immune cell infiltration in both normal and cancer tissues, especially in the stomach and colon. These findings proposed a possible fecal-oral and maternal-fetal transmission of SARS-CoV-2 and suggested that cancers of the respiratory, digestive or urinary tracts would be more vulnerable to SARS-CoV-2 infection.


Subject(s)
Computational Biology , Coronavirus Infections/immunology , Neoplasms/immunology , Pneumonia, Viral/immunology , Adult , Angiotensin-Converting Enzyme 2 , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Enterocytes/metabolism , Epithelial Cells/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Expression Regulation, Viral , Genotype , Goblet Cells/metabolism , Hepatocytes/metabolism , Humans , Immune System , Kidney Tubules/embryology , Male , Neoplasms/complications , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Prognosis , RNA-Seq , SARS-CoV-2 , Signal Transduction
12.
Mol Syst Biol ; 16(7): e9610, 2020 07.
Article in English | MEDLINE | ID: covidwho-680519

ABSTRACT

The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.


Subject(s)
Peptidyl-Dipeptidase A/metabolism , Respiratory System/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus , Blood Vessels/metabolism , Conjunctiva/metabolism , Enterocytes/metabolism , Female , Gallbladder/metabolism , Host Microbial Interactions , Humans , Immunohistochemistry , Kidney Tubules, Proximal/metabolism , Male , Mass Spectrometry , Myocytes, Cardiac/metabolism , Organ Specificity , Peptidyl-Dipeptidase A/genetics , Placenta/metabolism , Pregnancy , RNA-Seq , SARS-CoV-2 , Single-Cell Analysis , Testis/metabolism
13.
Genes (Basel) ; 11(6)2020 06 11.
Article in English | MEDLINE | ID: covidwho-602760

ABSTRACT

There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes ACE2 and TMPRSS2 throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing datasets from the GI tract were queried. Enterocytes from the small intestine and colonocytes showed the highest proportions of cells co-expressing ACE2 and TMPRSS2. Therefore, the lower GI tract represents the most likely site of SARS-CoV-2 entry leading to GI infection.


Subject(s)
Betacoronavirus/metabolism , Enterocytes/metabolism , Lower Gastrointestinal Tract/metabolism , Peptidyl-Dipeptidase A/genetics , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2 , Base Sequence , COVID-19 , Cells, Cultured , Coronavirus Infections/pathology , Enterocytes/virology , Gastrointestinal Diseases/virology , Humans , Lower Gastrointestinal Tract/virology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , SARS-CoV-2 , Sequence Analysis , Serine Endopeptidases/metabolism , Virus Internalization
15.
Science ; 369(6499): 50-54, 2020 07 03.
Article in English | MEDLINE | ID: covidwho-154670

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.


Subject(s)
Betacoronavirus/physiology , Enterocytes/virology , Ileum/virology , Virus Replication , Angiotensin-Converting Enzyme 2 , Betacoronavirus/ultrastructure , Cell Culture Techniques , Cell Differentiation , Cell Lineage , Cell Proliferation , Culture Media , Enterocytes/metabolism , Enterocytes/ultrastructure , Gene Expression , Humans , Ileum/metabolism , Ileum/ultrastructure , Lung/virology , Male , Organoids , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , Respiratory Mucosa/virology , SARS Virus/physiology , SARS-CoV-2
16.
Rev Esp Enferm Dig ; 112(5): 383-388, 2020 05.
Article in English | MEDLINE | ID: covidwho-148632

ABSTRACT

Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in angiotensin converting enzyme (ACE)-2 receptors. The initial gastrointestinal symptoms that appear early during the course of Covid-19 support this hypothesis. Furthermore, SARS-CoV virions are preferentially released apically and not at the basement of the airway cells. Thus, in the setting of a productive infection of conducting airway epithelia, the apically released SARS-CoV may be removed by mucociliary clearance and gain access to the GI tract via a luminal exposure. In addition, post-mortem studies of mice infected by SARS-CoV have demonstrated diffuse damage to the GI tract, with the small bowel showing signs of enterocyte desquamation, edema, small vessel dilation and lymphocyte infiltration, as well as mesenteric nodes with severe hemorrhage and necrosis. Finally, the small bowel is rich in furin, a serine protease which can separate the S-spike of the coronavirus into two "pinchers" (S1 and 2). The separation of the S-spike into S1 and S2 is essential for the attachment of the virion to both the ACE receptor and the cell membrane. In this special review, we describe the interaction of SARS-CoV-2 with the cell and enterocyte and its potential clinical implications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Enterocytes/virology , Gastrointestinal Diseases/virology , Intestine, Small/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/virology , Enterocytes/metabolism , Gastrointestinal Diseases/metabolism , Humans , Intestine, Small/cytology , Intestine, Small/metabolism , Pandemics , Pneumonia, Viral/virology , Receptors, Angiotensin/metabolism , Respiratory Mucosa/physiology , Respiratory Mucosa/virology , SARS-CoV-2
17.
Cell ; 181(5): 1016-1035.e19, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-100497

ABSTRACT

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.


Subject(s)
Alveolar Epithelial Cells/metabolism , Enterocytes/metabolism , Goblet Cells/metabolism , Interferon Type I/metabolism , Nasal Mucosa/cytology , Peptidyl-Dipeptidase A/genetics , Adolescent , Alveolar Epithelial Cells/immunology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/physiology , COVID-19 , Cell Line , Cells, Cultured , Child , Coronavirus Infections/virology , Enterocytes/immunology , Goblet Cells/immunology , HIV Infections/immunology , Humans , Influenza, Human/immunology , Interferon Type I/immunology , Lung/cytology , Lung/pathology , Macaca mulatta , Mice , Mycobacterium tuberculosis , Nasal Mucosa/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/genetics , SARS-CoV-2 , Serine Endopeptidases/metabolism , Single-Cell Analysis , Tuberculosis/immunology , Up-Regulation
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