Fear of mutations! The Chinese team revealed that exosomes can act as bait to block a variety of new coronavirus mutant strains

Since the outbreak of COVID-19 at the end of 2019, human health and lifestyles have been greatly affected. Despite the great success of the development of the COVID-19 vaccine, the control of the covid-19 epidemic remains a major global challenge due to the rapid mutation of the new coronavirus (SARS-CoV-2) and the slow pace of global vaccination. To better protect vulnerable unvaccinated and vaccinated populations, there is an urgent need to develop a new treatment to target the unpredictable coronavirus.

Recently, Northwestern University School of Medicine and the University of Texas MD Anderson Cancer Center jointly published a paper on Nature Communications, which found that evACE2 (extracellular vesicle of angiotensin-converting enzyme 2) can effectively block the infection of the new crown virus to host cells.

How does the coronavirus infect the human body? Similar to other coronaviruses, wild and mutant strains of the new coronavirus infect host cells, such as human lung cells, by entering the ACE2 (angiotensin-converting enzyme 2) receptor. Among them, the mutant strains of the new coronavirus pass through changes in viral proteins, such as the external receptor-binding domain (RBD) of the attachment protein (spike glycoprotein S), making it much more affinity with the ACE2 receptor than the wild strain. Therefore, some scientists have tried to use S-specific neutralizing antibodies and rhACE2 to block the action of the new coronavirus and the ACE2 receptor to achieve the purpose of inhibiting the infection of the new crown virus, but the clinical results have not been good.

In recent years, scientists have found that extracellular vesicles (EVs) are one of the important components of fluid biopsies such as blood and can participate in a variety of physiological and pathological biological functions. At the same time, there are a variety of proteins on the surface of the EV that are involved in the immune regulation of bone marrow and lymphocytes, and there are currently clinical trials to treat inflammation.

In the study, the researchers found a significant increase in evACE2 expression in blood circulation in PATIENTS WITH COVID-19, particularly in the acute phase. To measure evACE2 in the peripheral blood circulation of COVID-19 patients, the researchers established an automated high-throughput method, MVF, to detect and analyze the surface proteins of EVs in the blood at single-particle resolution. The results showed that evACE2 in the plasma of PATIENTS with COVID-19 was significantly elevated relative to healthy people, especially in patients in the acute phase, even in convalescent patients (Figure 1).

Figure 1 Expression of evACE2 in plasma of healthy populations, patients with new crown (acute phase), and patients with new crown (convalescent phase).

The researchers also found that evACE2 blocks the binding of the new coronavirus RBD to the host cell ACE2 receptor and mutant infection. To analyze the effects of evACE2 on viral attachment and infection, the researchers used flow cytometry to assess the binding effect of the new coronavirus to host cells. The results showed that the IC50 of EV1ACE2 and ev2ACE2 of HEK cells overexpressed with ACE2 and Hela cells was 77.06 pM and 87.16 pM, respectively, and the IC50 of rhACE2 was 10.37 nM. Thus, evACE2 blocks the binding of covid-19 RBD to human host cells 120-135 times more efficiently than rhACE2. The researchers further demonstrated that after infection with wild strains of the new coronavirus, evACE2 has a neutralizing effect of at least 80 times higher in its ability to block new coronavirus infection compared with rhACE2.

Figure 2 IC50 results of ev1ACE2, ev2ACE2, and rhACE2.

Based on the high expression of evACE2 in the plasma of covid-19 patients and its effect on blocking new coronavirus infection, the researchers tried to use evACE2 as a bait therapy for treating the new crown virus. The researchers used a mature mouse model of hACE2 transgenic mice to evaluate the efficacy of evACE2 preclinical treatment. The results showed that low-dose COVID-19 infections recovered completely within about 2 weeks, while high-dose COVID-19 infections had a high mortality rate due to severe lung injury. 80% of hACE2 mice treated with nasally delivered evACE2 (130 μg) were immune to death from COVID-19 infection (Figure 3).

Fig. 3 Disease-free survival in the evACE2 treatment group and control group.

In recent years, the COVID-19 pandemic has been threatening human health and causing great distress to people's normal work and life. Existing COVID-19 vaccines and therapeutic antibody drugs are being challenged by mutant strains, and a new real-world study in Israel shows that a fourth-shot booster injection is still not effective in preventing the rapidly spreading Omicron's breakthrough infection. The United States also suspended the Eli Lilly and Regeneron neocormab drugs in December 2021 due to their reduced efficacy against Omicron.

Almost all COVID-19 vaccines and therapeutic antibodies are S proteins against the virus, and despite the constant mutation of the new coronavirus, they still enter and infect human cells through the ACE2 receptor. EvACE2 competes with ACE2 on the surface of human cells as bait to attract the new crown virus, so no matter how the new crown virus mutates, it can effectively block its infection. Therefore, evACE2 is expected to become a new weapon to block the infection of the new crown virus, providing new hope for the success of the global fight against the epidemic.

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[1] El-Shennawy L, Hoffmann AD, Dashzeveg NK, et al. Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nat Commun. 2022 Jan 20;13(1):405.

Written by | Carrie Tan

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