Quotation: Fernbach S, Hale BG (2022) SARS-CoV-2 takes the bait: Exosomes as endogenous decoys. PLoS Biol 20(9):
e3001787.
https://doi.org/10.1371/journal.pbio.3001787
Revealed: September 14, 2022
Copyright: © 2022 Fernbach, Hale. That is an open entry article distributed beneath the phrases of the Artistic Commons Attribution License, which allows unrestricted use, distribution, and copy in any medium, supplied the unique writer and supply are credited.
Funding: Work within the BGH laboratory is funded by the Swiss Nationwide Science Basis by grant 31003A_182464 (to BGH). The funders had no position in research design, knowledge assortment and evaluation, resolution to publish, or preparation of the manuscript.
Competing pursuits: The authors have declared that no competing pursuits exist.
Abbreviations:
ACE2,
angiotensin changing enzyme 2; BALF,
bronchioalveolar lavage fluid; COVID-19,
Coronavirus Illness 2019; SARS-CoV-2,
Extreme Acute Respiratory Syndrome Coronavirus 2; TLR,
Toll-like receptor
From the start of the Coronavirus Illness 2019 (COVID-19) pandemic, researchers have studied numerous points of Extreme Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) biology. Amongst these, figuring out key host elements required for virus replication in human cells, in addition to assessing how the physique naturally fights an infection, have been vital to know pathogenesis, illness susceptibility, and therapeutic alternatives. Early on, cell floor localized host angiotensin changing enzyme 2 (ACE2) was recognized because the SARS-CoV-2 receptor obligatory for virus attachment to cells and the an infection course of [1,2]. Primarily based on this data, a number of research have designed novel therapy methods utilizing soluble or nanoparticle-displayed ACE2 as receptor decoys [3–5], with the purpose of sequestering SARS-CoV-2 particles away from genuine cell-expressed ACE2 and stopping an infection. These methods have proven success in preclinical research and might be a method to inhibit a broad vary of evolving SARS-CoV-2 variants which can be constrained of their widespread utilization of ACE2 [3–5].
Lending help to the idea of decoy-based therapy approaches in people, Ching and colleagues [6] now present proof that ACE2-decorated decoys are literally already an efficient characteristic of our physique’s personal innate immune arsenal of antiviral weapons towards SARS-CoV-2 (Fig 1). In earlier work, the identical group recognized a novel subset of exosomes (extracellular vesicles of endosomal origin with hallmark constituents and biogenesis routes [7]) which can be particularly produced by cells in response to bacterial an infection [8]. This subset of exosomes (termed “defensosomes”) integrated sometimes expressed cell floor protein receptors and thereby acted as decoys for bacterial toxins that will in any other case mediate toxicity by interacting with the identical protein receptors on the surfaces of dwelling cells [8]. Constructing upon this, the authors of the present research hypothesized that such “defensosomes” may also be produced in response to viruses and, in the event that they displayed adequate portions of the ACE2 receptor, may play a decoy position in defending cells towards SARS-CoV-2. To check this, the authors first obtained bronchioalveolar lavage fluid (BALF) samples from critically in poor health COVID-19 sufferers that had been admitted to intensive care and who required mechanical air flow. Utilizing biochemical fractionation and move cytometry, they enriched for exosomes in these samples and certainly discovered exosomes expressing ACE2. Curiously, the proportion of ACE2-positive exosomes, in addition to the quantity of ACE2 displayed on every exosome, different remarkably between people, and this allowed correlation analyses between ranges of ACE2-positive exosomes and numerous scientific parameters. Strikingly, sufferers with excessive quantities of ACE2-positive exosomes of their BALFs had been hospitalized for a shorter period than sufferers with low quantities of ACE2-positive exosomes and required fewer days of air flow, suggesting that ACE2-positive exosomes may certainly have a protecting position towards COVID-19.
To grasp how ACE2-positive exosomes may be produced within the respiratory tract, Ching and colleagues subsequent turned to in vitro cell-based methods and will present that SARS-CoV-2 an infection itself can set off their secretion. This virus-mediated induction has key hallmarks of being an lively host protection response to an infection, as just like bacterial induction it required host autophagy elements (notably ATG16L1) [8], and might be recapitulated by sure immune stimuli equivalent to Toll-like receptor (TLR) ligands. Curiously, nonetheless, activation of classical intracellular pattern-recognition receptors which can be concerned in different SARS-CoV-2 host responses, equivalent to cGAS, RIG-I, or MDA-5, didn’t result in elevated exosome manufacturing, suggesting a selected molecular mechanism linking infection-activated TLRs, the autophagy equipment, and “defensosomes” that awaits to be totally dissected. The potential position of interferons can be intriguing, but unresolved, as interferon signaling was apparently not required for TLR-mediated induction of exosomes, but low to reasonable quantities of interferons alone stimulated exosome manufacturing. Relating these observations again to affected person knowledge, the authors discovered that people with excessive quantities of ACE2-positive exosomes of their BALFs additionally had gene expression signatures for antiviral responses, additional strengthening the hyperlink between immune pathways and “defensosomes.”
Lastly, to check whether or not ACE2-positive exosomes can have a direct protecting impact on an infection final result, ACE2-positive or ACE2-negative exosomes had been remoted and incubated with SARS-CoV-2 previous to inoculation of extremely permissive cells in vitro. Solely ACE2-positive exosomes had been capable of inhibit SARS-CoV-2 infections, and cryo-electron microscopy and tomography revealed that these vesicles captured and clustered SARS-CoV-2 virus particles on their floor, seemingly by way of a direct ACE2–Spike (the virus attachment protein) interplay. These observations strongly help the idea that ACE2-positive exosomes can exert a decoy operate to dam an infection. Presumably, as soon as certain to decoy ACE2, the viral Spike protein undergoes an irreversible conformational change successfully inactivating virus infectivity, though the exact mechanisms await dedication.
General, the findings of Ching and colleagues, along with a current different research [9], make a compelling case for a brand new antiviral position of endogenous infection-triggered ACE2-positive “defensosomes” in controlling SARS-CoV-2 infections in people. These outcomes ought to encourage packages growing ACE2-based decoy therapies for COVID-19. The noticed interindividual variability in producing excessive amount and high quality protecting ACE2-positive exosomes is actually intriguing and will recommend that incapacity to mount an efficient “defensosome” response in some people may be one contributing issue to illness severity. The underlying foundation for such variability shall be necessary to find out if “defensosome” deficiencies are to be classed as predisposing to extreme viral infections like different immune deficiencies [10]. Nonetheless, as Ching and colleagues noticed, comorbidities equivalent to diabetes and/or hypertension appear to be related to decrease ranges of ACE2-positive exosomes, suggesting a posh multifactorial interaction that perhaps troublesome to untangle. Moreover, it’s attainable that ranges of ACE2-positive exosomes merely fluctuate over the course of an an infection (as steered in a cross-sectional research [9]), and variability between people might subsequently be influenced by time of sampling. Future longitudinal research may tackle this, and it could be attention-grabbing to evaluate whether or not some uninfected, wholesome people have elevated baseline ranges of “defensosomes” that provide a stage of intrinsic safety towards an infection. Such longitudinal research may be used to evaluate the prognostic worth of figuring out ACE2-positive exosome ranges for illness administration. As BALF samples could also be troublesome to acquire for such research, it’s noteworthy that ACE2-positive exosomes have additionally been noticed in additional readily accessible plasma samples [9]. Lastly, the work by Ching and colleagues has clear potential implications for virus infections past SARS-CoV-2, and research ought to now be undertaken to know higher the worldwide content material of particular “defensosomes,” for instance, to find out which host protein receptors are loaded into them, and whether or not it is a selective or random course of. Not solely will this be a place to begin to make clear molecular mechanisms regarding “defensosome” manufacturing, but it surely may additionally present vital insights into the spectrum of different pathogens which can be more likely to be inhibited by these endogenous decoys.
Fig 1. ACE2-positive exosomes are endogenous decoys that restrict SARS-CoV-2 an infection and COVID-19 severity.
An infection with SARS-CoV-2 triggers the manufacturing and launch of exosomes that categorical the SARS-CoV-2 receptor ACE2 on their floor. This course of is probably going depending on TLR signaling pathways and the autophagy element, ATG16L1. ACE2-positive exosomes act as decoys by binding SARS-CoV-2, thereby stopping viral particles from interacting with ACE2 expressed on the floor of naïve host cells. In BALFs from critically in poor health COVID-19 sufferers, the abundance of such ACE2-positive exosomes, in addition to the quantity of ACE2 expressed on every exosome, different significantly between people. Sufferers with increased ranges of ACE2-positive exosomes had been hospitalized for shorter occasions, and required fewer days of mechanical air flow, than sufferers with decrease ranges of ACE2-positive exosomes. This implies that endogenous ACE2-positive exosomes can have a protecting decoy position towards SARS-CoV-2 in people. ACE2, angiotensin changing enzyme 2; ATG16L1, Autophagy Associated 16 Like 1; BALF, bronchioalveolar lavage fluid; COVID-19, Coronavirus Illness 2019; SARS-CoV-2, Extreme Acute Respiratory Syndrome Coronavirus 2; TLR, Toll-like receptor.
