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1.
Viruses ; 14(3)2022 03 09.
Article in English | MEDLINE | ID: covidwho-1765951

ABSTRACT

Previously, the association between the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) and Dengue virus (DV) replication was demonstrated in liver cells and was found to be mediated at least by the interaction between DDC and phosphoinositide 3-kinase (PI3K). Here, we show that biogenic amines production and uptake impede DV replication in hepatocytes and monocytes, while the virus reduces catecholamine biosynthesis, metabolism, and transport. To examine how catecholamine biosynthesis/metabolism influences DV, first, we verified the role of DDC by altering DDC expression. DDC silencing enhanced virus replication, but not translation, attenuated the negative effect of DDC substrates on the virus and reduced the infection related cell death. Then, the role of the downstream steps of the catecholamine biosynthesis/metabolism was analyzed by chemical inhibition of the respective enzymes, application of their substrates and/or their products; moreover, reserpine, the inhibitor of the vesicular monoamine transporter 2 (VMAT2), was used to examine the role of uptake/storage of catecholamines on DV. Apart from the role of each enzyme/transporter, these studies revealed that the dopamine uptake, and not the dopamine-signaling, is responsible for the negative effect on DV. Accordingly, all treatments expected to enhance the accumulation of catecholamines in the cell cytosol suppressed DV replication. This was verified by the use of chemical inducers of catecholamine biosynthesis. Last, the cellular redox alterations due to catecholamine oxidation were not related with the inhibition of DV replication. In turn, DV apart from its negative impact on DDC, inhibits tyrosine hydroxylase, dopamine beta-hydroxylase, monoamine oxidase, and VMAT2 expression.


Subject(s)
Dengue , Dopamine , Catecholamines/metabolism , Dopamine/metabolism , Hepatocytes/metabolism , Humans , Phosphatidylinositol 3-Kinases/metabolism , Virus Replication
2.
Sci Rep ; 12(1): 1859, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1671609

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19). Transmembrane serine protease 2 (TMPRSS2) is a coreceptor. Abnormal hepatic function in COVID-19 suggests specific or bystander liver disease. Because liver cancer cells express the ACE2 viral receptor, they are widely used as models of SARS-CoV-2 infection in vitro. Therefore, the purpose of this study was to analyze ACE2 and TMPRSS2 expression and localization in human liver cancers and in non-tumor livers. We studied ACE2 and TMPRSS2 in transcriptomic datasets totaling 1503 liver cancers, followed by high-resolution confocal multiplex immunohistochemistry and quantitative image analysis of a 41-HCC tissue microarray. In cancers, we detected ACE2 and TMPRSS2 at the biliary pole of tumor hepatocytes. In whole mount sections of five normal liver samples, we identified ACE2 in hepatocyte's bile canaliculi, biliary epithelium, sinusoidal and capillary endothelial cells. Tumors carrying mutated ß-catenin showed ACE2 DNA hypomethylation and higher mRNA and protein expression, consistently with predicted ß-catenin response sites in the ACE2 promoter. Finally, ACE2 and TMPRSS2 co-expression networks highlighted hepatocyte-specific functions, oxidative stress and inflammation, suggesting a link between inflammation, ACE2 dysfunction and metabolic breakdown.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Carcinoma, Hepatocellular/metabolism , Hepatocytes/metabolism , Liver Neoplasms/metabolism , Receptors, Virus/metabolism , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , DNA Methylation , Gene Expression , Humans , Inflammation , Mutation , Oxidative Stress/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Virus/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , beta Catenin/genetics , beta Catenin/metabolism
3.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Article in English | MEDLINE | ID: covidwho-1642084

ABSTRACT

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants pose a challenge to controlling the COVID-19 pandemic. Previous studies indicate that clinical samples collected from individuals infected with the Delta variant may contain higher levels of RNA than previous variants, but the relationship between levels of viral RNA and infectious virus for individual variants is unknown. We measured infectious viral titer (using a microfocus-forming assay) and total and subgenomic viral RNA levels (using RT-PCR) in a set of 162 clinical samples containing SARS-CoV-2 Alpha, Delta, and Epsilon variants that were collected in identical swab kits from outpatient test sites and processed soon after collection. We observed a high degree of variation in the relationship between viral titers and RNA levels. Despite this, the overall infectivity differed among the three variants. Both Delta and Epsilon had significantly higher infectivity than Alpha, as measured by the number of infectious units per quantity of viral E gene RNA (5.9- and 3.0-fold increase; P < 0.0001, P = 0.014, respectively) or subgenomic E RNA (14.3- and 6.9-fold increase; P < 0.0001, P = 0.004, respectively). In addition to higher viral RNA levels reported for the Delta variant, the infectivity (amount of replication competent virus per viral genome copy) may be increased compared to Alpha. Measuring the relationship between live virus and viral RNA is an important step in assessing the infectivity of novel SARS-CoV-2 variants. An increase in the infectivity for Delta may further explain increased spread, suggesting a need for increased measures to prevent viral transmission.


Subject(s)
COVID-19/epidemiology , Gene Expression Regulation, Viral , Genome, Viral , RNA, Viral/genetics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Animals , COVID-19/pathology , COVID-19/transmission , COVID-19/virology , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/metabolism , Hepatocytes/metabolism , Hepatocytes/virology , Humans , RNA, Viral/metabolism , SARS-CoV-2/classification , SARS-CoV-2/metabolism , Vero Cells , Viral Load , Virulence
4.
Pharmacol Res Perspect ; 9(1): e00712, 2021 02.
Article in English | MEDLINE | ID: covidwho-1482163

ABSTRACT

Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites.


Subject(s)
Antiparasitic Agents/pharmacokinetics , Ivermectin/pharmacokinetics , Administration, Oral , Antiparasitic Agents/blood , Antiparasitic Agents/pharmacology , Cells, Cultured , Cytochrome P-450 Enzyme System/metabolism , Demethylation , Hepatocytes/metabolism , Humans , Hydroxylation , Ivermectin/blood , Ivermectin/pharmacology , Metabolic Networks and Pathways , Microsomes, Liver/metabolism
6.
Hepatology ; 74(4): 1825-1844, 2021 10.
Article in English | MEDLINE | ID: covidwho-1372726

ABSTRACT

BACKGROUND AND AIMS: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology. APPROACH AND RESULTS: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response. CONCLUSION: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.


Subject(s)
End Stage Liver Disease/pathology , Liver/pathology , Non-alcoholic Fatty Liver Disease/pathology , Organoids/metabolism , Adult , Aged , Biopsy , COVID-19/complications , COVID-19/virology , Cell Differentiation/immunology , End Stage Liver Disease/immunology , Female , Gene Expression Profiling , Healthy Volunteers , Hepatocytes/immunology , Hepatocytes/metabolism , Humans , Induced Pluripotent Stem Cells/immunology , Induced Pluripotent Stem Cells/metabolism , Liver/cytology , Liver/immunology , Liver Regeneration , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/immunology , Non-alcoholic Fatty Liver Disease/virology , Organoids/immunology , SARS-CoV-2/immunology , Up-Regulation/immunology
7.
Cell Mol Gastroenterol Hepatol ; 12(1): 141-157, 2021.
Article in English | MEDLINE | ID: covidwho-1307024

ABSTRACT

BACKGROUND & AIMS: Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. We aimed to determine if CD73 has nonredundant hepatoprotective functions. METHODS: Liver-specific CD73 knockout (CD73-LKO) mice were generated by targeting the Nt5e gene in hepatocytes. The CD73-LKO mice and hepatocytes were characterized using multiple approaches. RESULTS: Deletion of hepatocyte Nt5e resulted in an approximately 70% reduction in total liver CD73 protein (P < .0001). Male and female CD73-LKO mice developed normally during the first 21 weeks without significant liver phenotypes. Between 21 and 42 weeks, the CD73-LKO mice developed spontaneous-onset liver disease, with significant severity in male mice. Middle-aged male CD73-LKO mice showed hepatocyte swelling and ballooning (P < .05), inflammation (P < .01), and variable steatosis. Female CD73-LKO mice had lower serum albumin levels (P < .05) and increased inflammatory genes (P < .01), but did not show the spectrum of histopathologic changes in male mice, potentially owing to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice showed significant metabolic imbalance, with increased blood urea nitrogen (P < .0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypophosphorylation of AMPK substrates in CD73-LKO livers (P < .0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (P < .001). CONCLUSIONS: Hepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.


Subject(s)
5'-Nucleotidase/metabolism , Hepatocytes/metabolism , Homeostasis , Liver/metabolism , 5'-Nucleotidase/blood , 5'-Nucleotidase/deficiency , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Sex Characteristics
8.
Int J Mol Sci ; 22(6)2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1143521

ABSTRACT

SARS-CoV-2 infection can cause cytokine storm and may overshoot immunity in humans; however, it remains to be determined whether virus-induced soluble mediators from infected cells are carried by exosomes as vehicles to distant organs and cause tissue damage in COVID-19 patients. We took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and COVID-19 patients. Our results revealed that tenascin-C (TNC) and fibrinogen-ß (FGB) are highly abundant in exosomes from COVID-19 patients' plasma compared with that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via the Nuclear factor-κB (NF-κB) pathway, we examined the status of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-C motif chemokine ligand 5 (CCL5) expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase compared with that from healthy subjects. Together, our results demonstrate that TNC and FGB are transported through plasma exosomes and potentially trigger pro-inflammatory cytokine signaling in cells of distant organ.


Subject(s)
COVID-19/blood , Exosomes/chemistry , Exosomes/genetics , Fibrinogen/metabolism , Inflammation/metabolism , Tenascin/metabolism , Aged , COVID-19/complications , Cell Line , Chemokine CCL5/metabolism , Exosomes/metabolism , Exosomes/ultrastructure , Female , Hepatocytes/metabolism , Humans , Inflammation/etiology , Interleukin-6/metabolism , Male , Mass Spectrometry , Microscopy, Electron, Transmission , Middle Aged , NF-kappa B/metabolism , Protein Interaction Maps , Proteome/metabolism , Tumor Necrosis Factor-alpha/metabolism
9.
Expert Rev Vaccines ; 20(5): 623-634, 2021 05.
Article in English | MEDLINE | ID: covidwho-1118865

ABSTRACT

OBJECTIVE: Infectious disease emergencies like the 2013-2016 Ebola epidemic and the 2009 influenza and current SARS-CoV-2 pandemics illustrate that vaccines are now given to diverse populations with preexisting pathologies requiring pharmacological management. Many natural biomolecules (steroid hormones, fatty acids, vitamins) and ~60% of prescribed medications are processed by hepatic cytochrome P450 (CYP) 3A4. The objective of this work was to determine the impact of infection and vaccines on drug metabolism. METHODS: The impact of an adenovirus-based vaccine expressing Ebola glycoprotein (AdEBO) and H1N1 and H3N2 influenza viruses on hepatic CYP 3A4 and associated nuclear receptors was evaluated in human hepatocytes (HC-04 cells) and in mice. RESULTS: CYP3A activity was suppressed by 55% in mice 24 h after administration of mouse-adapted H1N1, while ˂10% activity remained in HC-04 cells after infection with H1N1 and H3N2 due to global suppression of cellular translation capacity, indicated by reduction (70%, H1N1, 56%, H3N2) of phosphorylated eukaryotic translation initiation factor 4e (eIF4E). AdEBO suppressed CYP3A activity in vivo (44%) and in vitro (26%) 24 hours after infection. CONCLUSION: As the clinical evaluation of vaccines for SARS-CoV-2 and other global pathogens rise, studies to evaluate the impact of new vaccines and emerging pathogens on CYP3A4 and other metabolic enzymes are warranted to avoid therapeutic failures that could further compromise the public health during infectious disease emergencies.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Hepatocytes/enzymology , Hepatocytes/metabolism , Liver/enzymology , Liver/metabolism , Pharmaceutical Preparations/metabolism , Animals , Cells, Cultured , Eukaryotic Initiation Factor-4E , Humans , Immunization/methods , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
10.
J Biol Chem ; 296: 100111, 2021.
Article in English | MEDLINE | ID: covidwho-1066049

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a ß-coronavirus, is the causative agent of the COVID-19 pandemic. Like for other coronaviruses, its particles are composed of four structural proteins: spike (S), envelope (E), membrane (M), and nucleoprotein (N) proteins. The involvement of each of these proteins and their interactions are critical for assembly and production of ß-coronavirus particles. Here, we sought to characterize the interplay of SARS-CoV-2 structural proteins during the viral assembly process. By combining biochemical and imaging assays in infected versus transfected cells, we show that E and M regulate intracellular trafficking of S as well as its intracellular processing. Indeed, the imaging data reveal that S is relocalized at endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) or Golgi compartments upon coexpression of E or M, as observed in SARS-CoV-2-infected cells, which prevents syncytia formation. We show that a C-terminal retrieval motif in the cytoplasmic tail of S is required for its M-mediated retention in the ERGIC, whereas E induces S retention by modulating the cell secretory pathway. We also highlight that E and M induce a specific maturation of N-glycosylation of S, independently of the regulation of its localization, with a profile that is observed both in infected cells and in purified viral particles. Finally, we show that E, M, and N are required for optimal production of virus-like-particles. Altogether, these results highlight how E and M proteins may influence the properties of S proteins and promote the assembly of SARS-CoV-2 viral particles.


Subject(s)
Coronavirus Envelope Proteins/genetics , Nucleocapsid Proteins/genetics , SARS-CoV-2/growth & development , Spike Glycoprotein, Coronavirus/genetics , Viral Matrix Proteins/genetics , Virion/growth & development , Virus Assembly/physiology , Animals , Biomimetic Materials/chemistry , Biomimetic Materials/metabolism , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Envelope Proteins/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum/virology , Gene Expression , Golgi Apparatus/metabolism , Golgi Apparatus/ultrastructure , Golgi Apparatus/virology , HEK293 Cells , Hepatocytes/metabolism , Hepatocytes/ultrastructure , Hepatocytes/virology , Host-Pathogen Interactions/genetics , Humans , Nucleocapsid Proteins/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Viral Matrix Proteins/metabolism , Virion/genetics , Virion/metabolism , Virus Internalization , Virus Release/physiology
11.
Theranostics ; 10(26): 12223-12240, 2020.
Article in English | MEDLINE | ID: covidwho-934619

ABSTRACT

Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-ß activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.


Subject(s)
COVID-19/metabolism , Hepacivirus/metabolism , Hepatitis C/metabolism , Mitogen-Activated Protein Kinase 14/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Adaptor Proteins, Signal Transducing/metabolism , Animals , COVID-19/virology , Chlorocebus aethiops , Enzyme Activation , HEK293 Cells , Hepatitis C/pathology , Hepatitis C/virology , Hepatocytes/metabolism , Humans , Imidazoles/pharmacology , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Phosphorylation , Pyridines/pharmacology , Vero Cells , Viral Core Proteins/metabolism , Virus Replication/drug effects
12.
Scand J Immunol ; 93(3): e12977, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-760191

ABSTRACT

In the natural history of SARS-CoV-2 infection, liver injury is frequent but quite mild and it is defined as any liver damage occurring during disease progression and treatment of infection in patients with or without pre-existing liver diseases. The underlying mechanisms for hepatic injury in patients with COVID-19 are still unclear but the liver damage in SARS-CoV-2 infection seems to be directly caused by virus-induced cytopathic effects. In this review, we will summarize all data of updated literature, regarding the relationship between SARS-CoV-2 infection, acute response and liver involvement. An overview will be given on liver injury, liver transplant and the possible consequences of COVID-19 in patients with pre-existing liver diseases.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Liver Diseases/immunology , Liver/immunology , SARS-CoV-2/immunology , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokines/immunology , Cytokines/metabolism , Hepatocytes/immunology , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver/pathology , Liver/physiopathology , Liver Diseases/physiopathology , Liver Diseases/therapy , Pandemics/prevention & control , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
13.
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
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