Bioengineered angiotensin-converting-enzyme-2: a potential therapeutic option against SARS-CoV-2 infection
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ABSTRACT:
SUBMITTER: Maiti B
PROVIDER: S-EPMC8589099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:COVID-19 is the newly born pandemic caused by the SARS-CoV-2 virus, which is the recently emerged betacoronavirus that crosses the species barrier. It predominantly infects pneumocytes of the respiratory tract, but due to the presence of angiotensin-converting enzyme II (ACE2) on other cells like surface enterocytes of the upper esophagus and colon, these are also considered as the primary sites of infection. ACE2 receptor served as a cellular entry point for SARS-CoV-2. The expression of the ACE2 receptors is regulated by several factors such as age, tobacco smoking, inflammatory signaling, ACE inhibitors, angiotensin receptor blockers, and comorbidities (chronic obstructive pulmonary disease (COPD), tuberculosis, cerebrovascular disease, coronary heart disease, hypertension, and diabetes). Therefore, scientists are trying to explore the in-depth knowledge of ACE2 and considered it as a potential indirect target for COVID-19 therapeutics. In this focused review, we discussed in detail ACE2 expressions and regulation by different factors in the primary or vulnerable sites of SARS-CoV-2 infections. Clinical trials of rhACE2 in COVID-19 patients are ongoing, and if the outcome of the trials proves positive, it will be a breakthrough for the management of COVID-19. Finally, we suggest that targeting the ACE2 (a master regulator) in a balanced way could serve as a potential option against the management of COVID-19.
| S-EPMC8265022 | biostudies-literature
Project description:COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Angiotensin-converting enzyme 2 (ACE2) is not only an enzyme but also a functional receptor on cell surfaces through which SARS-CoV-2 enters the host cells and is highly expressed in the heart, kidneys, and lungs and shed into the plasma. ACE2 is a key regulator of the renin-angiotensin-aldosterone system (RAAS). SARS-CoV-2 causes ACE/ACE2 balance disruption and RAAS activation, which leads ultimately to COVID-19 progression, especially in patients with comorbidities, such as hypertension, diabetes mellitus, and cardiovascular disease. Therefore, ACE2 expression may have paradoxical effects, aiding SARS-CoV-2 pathogenicity, yet conversely limiting viral infection. This article reviews the existing literature and knowledge of ACE2 in COVID-19 setting and focuses on its pathophysiologic involvement in disease progression, clinical outcomes, and therapeutic potential.
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Project description: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.
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Project description:Despite the availability of vaccines, COVID-19 continues to be aggressive, especially in immunocompromised individuals. Therefore, the development of a specific therapeutic agent with antiviral activity against SARS-CoV-2 is necessary. The infection pathway starts when the receptor binding domain of the viral spike protein interacts with the angiotensin converting enzyme 2 (ACE2), which acts as a host receptor for the RBD expressed on the host cell surface. In this scenario, ACE2 analogs binding to the RBD and preventing the cell entry can be promising antiviral agents. Most of the ACE2 residues involved in the interaction belong to the α1 helix, more specifically to the minimal fragment ACE2(24-42). In order to increase the stability of the secondary structure and thus antiviral activity, we designed different triazole-stapled analogs, changing the position and the number of bridges. The peptide called P3, which has the triazole-containing bridge in the positions 36-40, showed promising antiviral activity at micromolar concentrations assessed by plaque reduction assay. On the other hand, the double-stapled peptide P4 lost the activity, showing that excessive rigidity disfavors the interaction with the RBD.
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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.
| S-EPMC7892319 | biostudies-literature
Project description:The quick and advancing prevalence of the new coronavirus SARS-CoV-2 produced a global crisis surge with a profound impact on human health and worldwide economic constancy. The virus is known as one strain of coronavirus, which causes the respiratory infection responsible for the current pandemic of COVID-19. The virus spike protein has a high binding affinity to human ACE2, depending on crystallization analysis and biochemical interaction studies. Studies consistently reveal that rs2285666, a polymorphism found in ACE2, diverse significantly between Europeans and Asians, changing ACE2 expression. The alternating allele TT of rs2285666 SNP increased gene expression to 50%; thus, it may have a role in SARS-COV-2 infection vulnerability. This study aimed to investigate rs2285666 SNP association with SARS-CoV2 infection as a first report in the Iraqi population. Fifty (20 Male/30 Female) Covid-19 patients with severe symptoms with mean age (of 41.5±10.7) and 50 (20 Male/30 Female) healthy people as a control group with mean age (of 41.5±10.7) were included in this study. Sample of a patient tested as a mutant genotype (TT) by RFLP assay. The results reveal a MAF value of 0.3 for this gene in Iraqi samples, more than Europeans (0.2) and less than East Asians (0.55). The codominant model had significant OR of both alleles CT and TT (OR=4.26 & 6.7; P-value=0.012 & 0.023 respectively). In conclusion, there is an association between increased severity of SARS-Cov-2 infection and rs2285666 polymorphism of the codominant genotype model of the Iraqi population. However, several other factors may affect disease severity, such as ethnic group differences, sex, comorbidity, virus strain, and others.
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