Endogenous exosomes act as decoys for SARS-CoV-2

A recent study published in the journal Plus Biology Exosomes discussed as potential hoaxes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Stady: SARS-CoV-2 takes the bait: Exosomes like self-deceptions. Image Credit: Miletius Veras / Shutterstock

background

SARS-CoV-2 has been extensively studied since the beginning of the coronavirus disease 2019 (COVID-19) pandemic. Identification of host factors involved in viral replication and assessment of immune responses has been pivotal in exploring pathogenesis, susceptibility to COVID-19, and therapeutics. Initial studies identified angiotensin-converting enzyme 2 (ACE2) on the human cell surface as a host receptor for SARS-CoV-2.

Multiple reports indicate novel strategies for using ACE2 receptors as decoys in the form of soluble or nanoparticle (NP) exhibited to isolate SARS-CoV-2 viruses away from native ACE2 expressed on cells and prevent infection. The success of this approach has been demonstrated by several preclinical studies, which could constitute a broad therapeutic option for mutant SARS-CoV-2 variants, which typically use the ACE2 receptor.

In a study, researchers at the University of Zurich, Switzerland, identified a subgroup of exosomes, called defensosomes, that are specifically secreted during bacterial infections. These dysnososomes incorporated surface receptors to levels normally expressed in cells and acted as decoys of bacterial toxins, which would otherwise have mediated toxicity through interactions with receptors on living cells.

ACE2-coated exosomes in COVID-19 patients

Based on this evidence, the researchers in that study concluded that these defenses may also form in response to viral infections. If adequate levels of ACE-2 are displayed, defenses can act as decoys for SARS-CoV-2. To this end, they tested bronchoalveolar lavage fluid (BALF) samples collected from critically ill COVID-19 patients under intensive care and mechanical ventilation.

Exosomes were enriched in (BALF) samples using flow cytometry and biochemical fractionation. Exosomes expressing ACE2 were observed, and interestingly, the proportion of exosomes decorated with ACE2 and the levels of ACE2 per exosome differed markedly between individuals. Correlation analyzes revealed that for patients with high ACE2-expressing exosomes, hospital stays were shorter with less time to ventilation than those with low levels of ACE2-coated exosomes, suggesting a protective role for defenses.

SARS-CoV-2 infection triggers the release of ACE2 .-coated defenses

Next, they showed that SARS-CoV-2 can trigger the secretion of ACE2-coated exosomes in cell-based assays. in the laboratory. This induction was similar to bacterial induction in that both components required autophagy for the host and were summed up by some immune stimuli. However, activation of pattern recognition receptors (PRRs) in response to SARS-CoV-2 did not lead to increased exocytosis, suggesting a specific mechanism that binds the receptors TLRs, defensosomes, and components of autophagy.

Furthermore, the researchers isolated ACE2-positive and negative exosomes and incubated them with SARS-CoV-2 before inoculating the allowable cells. Only exosomes expressing ACE2 prevented viral infection. Tomography and cryo-electron microscopy analyzes indicated the capture and assembly of viral particles on the surface through a direct interaction between the viral spike and ACE2.

ACE2-positive exosomes are internal decoys that limit SARS-CoV-2 infection and the severity of COVID-19.  Infection with SARS-CoV-2 leads to the production and release of exosomes that express the SARS-CoV-2 receptor ACE2 on their surface.  This process likely depends on the TLR signaling pathways and the autophagy component ATG16L1.  ACE2-positive exosomes act as decoys by binding SARS-CoV-2, thus preventing viral particles from interacting with ACE2 expressed on the surface of naive host cells.  In BALFs from critically ill COVID-19 patients, the abundance of these ACE2-positive exosomes, as well as the amount of ACE2 expressed in each exosome, varied significantly between individuals.  Patients with higher levels of ACE2-positive exosomes were hospitalized for shorter periods and required fewer days of mechanical ventilation than patients with lower levels of ACE2-positive exosomes.  This indicates that endogenous ACE-2 exosomes could have a protective role against SARS-CoV-2 in humans.  ACE2, angiotensin-converting enzyme 2;  ATG16L1, autophagy related 16 as 1;  BALF, bronchoalveolar lavage fluid;  COVID-19, coronavirus disease 2019;  SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2;  TLR, a future like Toll.ACE2-positive exosomes are internal decoys that limit SARS-CoV-2 infection and the severity of COVID-19. Infection with SARS-CoV-2 leads to the production and release of exosomes that express the SARS-CoV-2 receptor ACE2 on their surface. This process likely depends on the TLR signaling pathways and the autophagy component ATG16L1. ACE2-positive exosomes act as decoys by binding SARS-CoV-2, thus preventing viral particles from interacting with ACE2 expressed on the surface of naive host cells. In BALFs from critically ill COVID-19 patients, the abundance of these ACE2-positive exosomes, as well as the amount of ACE2 expressed in each exosome, varied significantly between individuals. Patients with higher levels of ACE2-positive exosomes were hospitalized for shorter periods and required fewer days of mechanical ventilation than patients with lower levels of ACE2-positive exosomes. This indicates that endogenous ACE-2 exosomes could have a protective role against SARS-CoV-2 in humans. ACE2, angiotensin-converting enzyme 2; ATG16L1, autophagy related 16 as 1; BALF, bronchoalveolar lavage fluid; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2; TLR, a future like Toll.

concluding remarks

In summary, the results indicate novel antiviral activity of ACE2-decorated endogenous antivirals against SARS-CoV-2, thus encouraging the development of ACE2-based therapies for COVID-19.

Notably, interindividual variability in the secretion of protective ACE2 defenses suggests that the inability to mount an appropriate defense response may contribute to the severity of COVID-19. However, further studies are needed to understand the content of specific defenses and to determine which host receptors are expressed and whether this is a stochastic or selective mechanism.