Role of ACE2 in Coronavirus Infection
The SARS-CoV-2 virus particle is covered in spines. Coronavirus infection occurs when a viral spike protein (S) interacts with a receptor on the cell’s surface. The SARS-CoV-2 coronavirus uses human angiotensin-converting enzyme 2 (hACE2, ACE2) as a receptor for infecting cells.
Protein ACE2 reduces the activity of the renin-angiotensin-aldosterone system (RAAS) – lowers blood pressure. It is ubiquitously expressed in the heart, blood vessels, intestines, lungs, liver, kidneys, testes, and brain. To regulate RAAS, ACE2 breaks down the angiotensin II protein (Ang 2) to Ang 1-7. The resulting Ang 1-7 has vasodilating, anti-inflammatory, anti-fibrotic and antiproliferative effects. Since ACE2 is a potent regulator of pathological changes in several organs, including the lungs, heart, testes and kidneys, its expression is closely related to the clinical symptoms of COVID-19.
Since the SARS-CoV-2 S protein binds to ACE2 through membrane fusion, SARS-CoV-2 infection suppresses ACE2. It can lead to increased inflammation, vasoconstriction and thrombosis. Patients with severe COVID-19 and medical conditions such as hypertension, diabetes and cardiovascular disease have ACE2 deficiency. That confirms the pivotal role of ACE2 in COVID-19.
Studies have shown that recombinant ACE2 (rACE2) protects the lungs from damage, and human recombinant soluble ACE2 (hrsACE2) inhibits SARS-CoV-2 infection in Vero cells and engineered organelles of human blood vessels and kidneys. It confirms that ACE2 plays a critical role in COVID-19 therapy.
The Body Protects Itself Against The Virus by Producing Interferon
In response to a viral infection, the body’s cells produce type I interferon (IFN). IFN-I protects the body from viruses and stimulates the adaptive immune response. IFN-I triggers the expression of genes ISG – genes stimulated by interferon that play a critical role in the antiviral response. Many viruses can evade the interferon response. Therefore, the introduction of IFN-I or molecules that mimic the IFN response opens up new treatment options.
Exosomes are a Possible Treatment Tool for COVID-19
Exosomes are vesicles that are secreted by cells to act on the extracellular environment. Inside the membrane of exosomes are proteins and nucleic acids. Other cells consume exosomes and change their properties.
Exosomes play an essential role in treating many diseases, including cancer, cardiovascular disease, pathogenic infections, and migraines. Exosomes can serve as carriers of vaccines and drugs. Chinese scientists have investigated whether exosomes can be used to treat COVID-19.
ACE2 is Expressed on The Surface of Exosomes. Interferon-Alpha/Beta Increases ACE2 Expression
IFN-I plays a crucial role during the initial defense of the body against a viral attack. Studies have shown that treatment with IFN-alpha/beta can suppress the replication of SARS-CoV-2 in vitro and in vivo. It indicates a critical role for IFN-I in the treatment of SARS-CoV-2 coronavirus.
Scientists have found that IFN-alpha and IFN-beta stimulate ACE2 expression in human embryonic kidney cells (HEK293T) and human respiratory tract cell lines, including human bronchial epithelial cells (16HBE) and lung carcinoma cells (H1299).
Through a series of experiments, the scientists showed that ACE2 is expressed on the cell surface and the surface of exosomes from various cell lines, including HEK293T, 16HBE, and H1299.
Treatment of cells with IFN-alpha and IFN-beta increased both cellular and exosomal ACE2 from HEK293T and 16HBE cells. IFN-beta stimulated the expression of exosomal ACE2 in a dose-dependent manner.
Cells have a mechanism by which they sort the contents of exosomes – the ESCRT protein complex. One of the ESCRT proteins is Hrs. Depletion of the Hrs protein reduces exosome secretion. Scientists have shown that IFN-beta-induced upregulation of exosomal ACE2 declines after lack of Hrs.
Increased ACE2 as an Antiviral Mechanism
The increase in ACE2 expression under the influence of type I interferon seems illogical since interferon is well known for its antiviral activity. It is unlikely that IFN promotes viral penetration by enhancing the expression of the viral ACE2 receptor on the cell surface.
Scientists have suggested that the increase in ACE2 is an antiviral mechanism. They co-cultured exosomes that expressed ACE2 on the surface with SARS-CoV-2-S/HIV-1 viral particles. The penetration of viral particles into cells has been significantly reduced. Exosomes isolated from cells stimulated with IFN-alpha/beta also reduced the penetration of SARS-CoV-2-S/HIV-1 viral particles into cells. Experimental data showed that exosomal ACE2 suppressed the penetration of viral particles into cells with a dose-dependent effect.
Scientists have found that coronavirus-infected cells also secrete exosomes containing ACE2. This mechanism suppresses SARS-CoV-2 infection in vitro.
Experiment on mice. Human ACE2 transgenic mice (hACE2 mice) are highly susceptible to SARS-CoV-2 infection. Scientists pretreated SARS-CoV-2 virus particles with empty exosomes or exosomes with ACE2 and then intranasally infected hACE2 mice. On the fifth day, a lower viral load in the lungs was in mice infected with SARS-CoV-2, pretreated with exosomes with ACE2. SARS-CoV-2 infection can cause fatal inflammatory reactions and acute lung damage. Mice infected with SARS-CoV-2 pretreated with exosomes with ACE2 had lower expression of pro-inflammatory cytokines and chemokines and minor pneumonia.
Exosomal ACE2 can interact with the S-protein on the surface of SARS-CoV-2-S / HIV-1 viral particles and with the S-protein’s purified receptor-binding domain (RBD). Notably, wild-type SARS-CoV-2 replication was also inhibited in vitro and ex vivo after co-cultivation with ACE2 exosomes.
The scientists concluded that exosomal ACE2 competes with cellular ACE2 to bind to a viral particle and block the virus’s entry into the cell. Exosomal ACE2 suppresses SARS-CoV-2 infection in vitro and ex vivo, and ACE2 exosomes can treat COVID-19.
Conclusions
Suppressing SARS-CoV-2 infection with exosomal ACE2 could be a new treatment for coronavirus as it blocks SARS-CoV-2 from entering the cell without decreasing ACE2 levels.
Inhalation using naturally secreted lung spheroid cell-derived exosomes (LSC-Exo) promotes lung recovery in fibrosis. Since ACE2 is a crucial regulator of lung pathology and protects the lungs from damage, the results of this study may partially explain the mechanism by which LSC-Exo promotes lung recovery.
Based on the results of this study, scientists have proposed using modified exosomes with increased expression of ACE2 or exosomes containing exogenous anti-coronavirus drugs for the treatment of SARS-CoV-2 coronavirus. Inhaling LSC-Exo with ACE2 can be a safe and effective way to treat coronavirus, as SARS-CoV-2 mainly enters the body through the respiratory tract.
Type I interferons are approved to treat many diseases, including viral infections (hepatitis B and C), autoimmune diseases, and some cancers, and are currently being used in clinical trials to treat MERS-CoV and SARS-CoV-2.
ACE2 is an interferon-stimulated gene. IFN-I and IFN-III trigger its expression in primary basal cells of the human upper respiratory tract. The present study’s data also showed that the expression of ACE2 in human respiratory tract cell lines and human embryonic kidney cells is stimulated by IFN-I.
ACE2 is expressed in exosomes, and its expression is increased by type I interferon. Exosomal ACE2 suppresses SARS-CoV-2 infection. Therefore, ACE2-exosomes and IFN-stimulated exosomes can be an effective tool for the treatment of SARS-CoV-2 disease.
