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1.
Sci Immunol ; 7(67): eabl9929, 2022 Jan 28.
Article in English | MEDLINE | ID: covidwho-1673341

ABSTRACT

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model's usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2­infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/physiopathology , Disease Models, Animal , Encephalitis, Viral/prevention & control , Keratin-18/genetics , Nasal Sprays , SARS-CoV-2/physiology , Administration, Inhalation , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/virology , Encephalitis, Viral/mortality , Epithelial Cells/metabolism , Female , Humans , Keratin-18/metabolism , Lung/immunology , Lung/pathology , Lung/physiopathology , Male , Mice , Mice, Transgenic , Promoter Regions, Genetic/genetics , Transcriptome , Virus Replication
2.
Cytokine ; 148: 155697, 2021 12.
Article in English | MEDLINE | ID: covidwho-1385382

ABSTRACT

The prevalence of SARS-CoV-2 is a great threat to global public health. However, the relationship between the viral pathogen SARS-CoV-2 and host innate immunity has not yet been well studied. The genome of SARS-CoV-2 encodes a viral protease called 3C-like protease. This protease is responsible for cleaving viral polyproteins during replication. In this investigation, 293T cells were transfected with SARS-CoV-2 3CL and then infected with Sendai virus (SeV) to induce the RIG-I like receptor (RLR)-based immune pathway. q-PCR, luciferase reporter assays, and western blotting were used for experimental analyses. We found that SARS-CoV-2 3CL significantly downregulated IFN-ß mRNA levels. Upon SeV infection, SARS-CoV-2 3CL inhibited the nuclear translocation of IRF3 and p65 and promoted the degradation of IRF3. This effect of SARS-CoV-2 3CL on type I IFN in the RLR immune pathway opens up novel ideas for future research on SARS-CoV-2.


Subject(s)
Coronavirus 3C Proteases/metabolism , Interferon Regulatory Factor-3/metabolism , Interferon-beta/biosynthesis , Proteolysis , DEAD Box Protein 58/metabolism , Gene Expression Regulation , HEK293 Cells , Humans , Interferon-beta/genetics , NF-kappa B/genetics , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Immunologic/metabolism , Response Elements/genetics , Sendai virus/physiology , Signal Transduction
3.
Stem Cell Rev Rep ; 17(6): 2164-2177, 2021 12.
Article in English | MEDLINE | ID: covidwho-1279489

ABSTRACT

Stress-induced changes in viral receptor and susceptibility gene expression were measured in embryonic stem cells (ESC) and differentiated progeny. Rex1 promoter-Red Fluorescence Protein reporter ESC were tested by RNAseq after 72hr exposures to control stress hyperosmotic sorbitol under stemness culture (NS) to quantify stress-forced differentiation (SFD) transcriptomic programs. Control ESC cultured with stemness factor removal produced normal differentiation (ND). Bulk RNAseq transcriptomic analysis showed significant upregulation of two genes involved in Covid-19 cell uptake, Vimentin (VIM) and Transmembrane Serine Protease 2 (TMPRSS2). SFD increased the hepatitis A virus receptor (Havcr1) and the transplacental Herpes simplex 1 (HSV1) virus receptor (Pvrl1) compared with ESC undergoing ND. Several other coronavirus receptors, Glutamyl Aminopeptidase (ENPEP) and Dipeptidyl Peptidase 4 (DPP4) were upregulated significantly in SFD>ND. Although stressed ESC are more susceptible to infection due to increased expression of viral receptors and decreased resistance, the necessary Covid-19 receptor, angiotensin converting enzyme (ACE)2, was not expressed in our experiments. TMPRSS2, ENPEP, and DPP4 mediate Coronavirus uptake, but are also markers of extra-embryonic endoderm (XEN), which arise from ESC undergoing ND or SFD. Mouse and human ESCs differentiated to XEN increase TMPRSS2 and other Covid-19 uptake-mediating gene expression, but only some lines express ACE2. Covid-19 susceptibility appears to be genotype-specific and not ubiquitous. Of the 30 gene ontology (GO) groups for viral susceptibility, 15 underwent significant stress-forced changes. Of these, 4 GO groups mediated negative viral regulation and most genes in these increase in ND and decrease with SFD, thus suggesting that stress increases ESC viral susceptibility. Taken together, the data suggest that a control hyperosmotic stress can increase Covid-19 susceptibility and decrease viral host resistance in mouse ESC. However, this limited pilot study should be followed with studies in human ESC, tests of environmental, hormonal, and pharmaceutical stressors and direct tests for infection of stressed, cultured ESC and embryos by Covid-19.


Subject(s)
COVID-19/genetics , COVID-19/virology , Host Microbial Interactions/genetics , Mouse Embryonic Stem Cells/virology , Animals , Cell Differentiation/genetics , Cells, Cultured , Gene Expression/genetics , Humans , Mice , Pilot Projects , Promoter Regions, Genetic/genetics , SARS-CoV-2/pathogenicity
4.
Cells ; 10(4)2021 04 15.
Article in English | MEDLINE | ID: covidwho-1232577

ABSTRACT

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1-ERK1/2-AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.


Subject(s)
Gene Expression Regulation , Neovascularization, Physiologic/genetics , Thrombin/pharmacology , Transcription, Genetic/drug effects , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation/drug effects , Humans , Microvessels/pathology , Neovascularization, Physiologic/drug effects , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-jun/metabolism , Receptor, PAR-1/metabolism , Transcription Factor AP-1/metabolism , Vascular Endothelial Growth Factor A/genetics
5.
Biochem Biophys Res Commun ; 553: 25-29, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1147359

ABSTRACT

The current COVID-19 pandemic is caused by infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A sex-bias has been observed, with increased susceptibility and mortality in male compared to female patients. The gene for the SARS-CoV-2 receptor ACE2 is located on the X chromosome. We previously generated TP53 mutant pigs that exhibit a sex-specific patho-phenotype due to altered regulation of numerous X chromosome genes. In this study, we explored the effect of p53 deficiency on ACE2 expression in pigs. First, we identified the p53 binding site in the ACE2 promoter and could show its regulatory effect on ACE2 expression by luciferase assay in porcine primary kidney fibroblast cells. Later, quantitative PCR and western blot showed tissue- and gender-specific expression changes of ACE2 and its truncated isoform in p53-deficient pigs. We believe these findings will broaden the knowledge on ACE2 regulation and COVID-19 susceptibility.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Gene Expression Regulation , Organ Specificity , Sex Characteristics , Sus scrofa/metabolism , Tumor Suppressor Protein p53/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Animals , Base Sequence , Binding Sites , COVID-19/metabolism , COVID-19/virology , Disease Models, Animal , Female , Fibroblasts , Gene Deletion , Male , Promoter Regions, Genetic/genetics , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , X Chromosome/genetics
6.
Can J Physiol Pharmacol ; 99(5): 449-460, 2021 May.
Article in English | MEDLINE | ID: covidwho-1125455

ABSTRACT

Ribavirin is a guanosine analog with broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico, and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection, whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that ribavirin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, ribavirin was shown to decrease the expression of TMPRSS2 at both mRNA and protein levels 48 h after treatment. The suppressive effect of ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that ribavirin also showed an inhibitory effect on the TMPRSS2 enzyme. Based on these results, we hypothesized that ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effects of TMPRSS2 and ACE2 expression.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Down-Regulation/drug effects , Ribavirin/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Caco-2 Cells , Chlorocebus aethiops , G-Quadruplexes/drug effects , Humans , Promoter Regions, Genetic/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Vero Cells
7.
J Cell Mol Med ; 25(8): 4157-4165, 2021 04.
Article in English | MEDLINE | ID: covidwho-1091045

ABSTRACT

TMPRSS2 (OMIM: 602060) is a cellular protease involved in many physiological and pathological processes, and it facilitates entry of viruses such as SARS-CoV-2 into host cells. It is important to predict the prostate's susceptibility to SARS-CoV-2 infection in cancer patients and the disease outcome by assessing TMPRSS2 expression in cancer tissues. In this study, we conducted the expression profiles of the TMPRSS2 gene for COVID-19 in different normal tissues and PRAD (prostate adenocarcinoma) tumour tissues. TMPRSS2 is highly expressed in normal tissues including the small intestine, prostate, pancreas, salivary gland, colon, stomach, seminal vesicle and lung, and is increased in PRAD tissues, indicating that SARS-CoV-2 might attack not only the lungs and other normal organs, but also in PRAD cancer tissues. Hypomethylation of TMPRSS2 promoter may not be the mechanism for TMPRSS2 overexpression in PRAD tissues and PRAD pathogenesis. TMPRSS2 expresses eleven isoforms in PRAD tissues, with the TMPRSS2-001 isoform expressed highest and followed by TMPRSS2-201. Further isoform structures prediction showed that these two highly expressed isoforms have both SRCR_2 and Trypsin (Tryp_SPc) domains, which may be essential for TMPRSS2 functional roles for tumorigenesis and entry for SARS-CoV-2 in PRAD patients. Analyses of functional annotation and enrichment in TMPRSS2 showed that TMPRSS2 is mostly enriched in regulation of viral entry into host cells, protein processing and serine-type peptidase activity. TMPRSS2 is also associated with prostate gland cancer cell expression, different complex(es) formation, human influenza and carcinoma, pathways in prostate cancer, influenza A, and transcriptional misregulation in cancer. Altogether, even though high expression of TMPRSS2 may not be favourable for PRAD patient's survival, increased expression in these patients should play roles in susceptibility of the SARS-CoV-2 infection and clinical severity for COVID-19, highlighting the value of protective actions of PRAD cases by targeting or androgen-mediated therapeutic strategies in the COVID-19 pandemic.


Subject(s)
Adenocarcinoma/genetics , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Prostatic Neoplasms/genetics , SARS-CoV-2/isolation & purification , Serine Endopeptidases/genetics , Adenocarcinoma/metabolism , COVID-19/metabolism , COVID-19/virology , DNA Methylation , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Gene Ontology , Humans , Kaplan-Meier Estimate , Male , Promoter Regions, Genetic/genetics , Prostate/metabolism , Prostatic Neoplasms/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism
8.
Curr Cancer Drug Targets ; 21(5): 428-442, 2021 07 05.
Article in English | MEDLINE | ID: covidwho-969514

ABSTRACT

BACKGROUND: A higher incidence of COVID-19 infection was demonstrated in cancer patients, including lung cancer patients. This study was conducted to get insights into the enhanced frequency of COVID-19 infection in cancer. METHODS: Using different bioinformatics tools, the expression and methylation patterns of ACE2 and TMPRSS2 were analyzed in healthy and malignant tissues, focusing on lung adenocarcinoma and data were correlated to clinical parameters and smoking history. RESULTS: ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression levels in digestive, urinary and reproductive organs, while the overall analysis of 72 paired tissues demonstrated significantly lower expression levels of ACE2 in cancer tissues when compared to normal counterparts. In contrast, ACE2, but not TMPRSS2, was overexpressed in LUAD, which inversely correlated to the promoter methylation. This upregulation of ACE2 was age-dependent in LUAD, but not in normal lung tissues. TMPRSS2 expression in non-neoplastic lung tissues was heterogeneous and dependent on sex and smoking history, while it was downregulated in LUAD of smokers. Cancer progression was associated with a decreased TMPRSS2 but unaltered ACE2. In contrast, ACE2 and TMPRSS2 of lung metastases derived from different cancer subtypes was higher than organ metastases of other sites. TMPRSS2, but not ACE2, was associated with LUAD patients' survival. CONCLUSIONS: Comprehensive molecular analyses revealed a heterogeneous and distinct expression and/or methylation profile of ACE2 and TMPRSS2 in healthy lung vs. LUAD tissues across sex, age and smoking history and might have implications for COVID-19 disease.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Lung Neoplasms/epidemiology , Lung Neoplasms/genetics , Lung/virology , Adenocarcinoma of Lung/epidemiology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/virology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/virology , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Lung Neoplasms/virology , Methylation , Promoter Regions, Genetic/genetics , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Smoking/adverse effects , Up-Regulation/genetics
9.
Immunol Invest ; 51(3): 546-557, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-969122

ABSTRACT

BACKGROUND: Tumor necrosis factor-ɑ (TNF-ɑ) is one of the most important cytokines that manage the host defense mechanism, which may play a role in the pathogenesis of COVID-19 patients. The work aims to study the association of TNF-ɑ G-308 A gene polymorphism with the course and outcome of COVID-19 patients in Mansoura University Hospital. METHODS: 900 patients with COVID-19 infection and 184 controls were tested for TNF-ɑ G-308 A promoter polymorphism. Different genotypes of TNF-ɑ G-308 A were compared as regards the severity and prognosis of the disease. RESULTS: No statistically significant difference was found between patients and controls as regards the demographic data. The AA genotype of TNF-ɑ showed a higher incidence of the disease in comparison to the other genotypes. As regards the demographic and laboratory characters, no statistically significant difference was found between the different genotypes except for age, lymphopenia, CRP, and serum ferritin levels. In 336(80.0%) cases of the AA genotype, the disease was severe in comparison to 90(41.7%) cases in the GA genotype and no cases in the GG genotype with P = .001. CONCLUSION: People who carry the A allele of TNF-ɑ polymorphism are more prone to COVID-19 infection. The AA genotype of TNF-ɑ is associated with a more aggressive pattern of the disease. In those patients, the use of anti - TNF therapy may be promising.


Subject(s)
COVID-19 , Tumor Necrosis Factor-alpha , COVID-19/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Humans , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Tumor Necrosis Factor-alpha/genetics
10.
Nat Commun ; 11(1): 6122, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-952011

ABSTRACT

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Disease Models, Animal , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , Brain/immunology , Brain/pathology , Brain/virology , COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Disease Susceptibility , Genetic Predisposition to Disease , Keratin-18/genetics , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Mortality , Promoter Regions, Genetic/genetics , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , Virus Diseases/immunology , Virus Diseases/pathology
11.
Nat Immunol ; 21(11): 1327-1335, 2020 11.
Article in English | MEDLINE | ID: covidwho-728991

ABSTRACT

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Immunity, Innate/immunology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Pneumonia/pathology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/immunology , Disease Models, Animal , Female , Humans , Interferon Type I/immunology , Interferon-gamma/immunology , Keratin-18/genetics , Leukocytes/immunology , Lymphocyte Activation/immunology , Male , Mice , Mice, Transgenic , Monocytes/immunology , NF-kappa B/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pandemics , Pneumonia/genetics , Pneumonia/virology , Pneumonia, Viral/immunology , Promoter Regions, Genetic/genetics , SARS-CoV-2 , T-Lymphocytes/immunology , Vero Cells , Virus Replication/immunology
12.
Trends Genet ; 36(11): 813-815, 2020 11.
Article in English | MEDLINE | ID: covidwho-704022

ABSTRACT

Based on a broad public database compilation, we support the hypothesis that germinal polymorphisms may regulate the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular target itself and proteases controlling the process of its shedding or, conversely, its internalization. Consequently, a genetic influence on individual susceptibility to coronavirus disease 2019 (COVID-19) infection is strongly suspected.


Subject(s)
ADAM17 Protein/genetics , Betacoronavirus/physiology , Coronavirus Infections/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Polymorphism, Genetic/genetics , Serine Endopeptidases/genetics , ADAM17 Protein/metabolism , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/virology , Disease Susceptibility , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/genetics , SARS-CoV-2 , Serine Endopeptidases/metabolism , Virus Internalization , Virus Shedding
14.
Hum Genomics ; 14(1): 20, 2020 06 04.
Article in English | MEDLINE | ID: covidwho-526827

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and other epithelia and have shown to develop a rapidly lethal infection after intranasal inoculation with SARS-CoV, the pathogen of SARS. This literature review aims to present the importance of utilizing the human ACE2 transgenic mouse model to better understand the pathogenesis of COVID-19 and develop both therapeutics and vaccines.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/pathogenicity , COVID-19 , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pandemics , Promoter Regions, Genetic/genetics , Protein Binding/physiology , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2
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