Circulating ACE2-expressing Extracellular Vesicles as an Innate Antiviral Response and A Decoy Therapy to Block Broad Strains of SARS-CoV-2

ABSTRACT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with 216 million cases and 4.5 million deathsas of September 2021.Thathas been exacerbated by mutated variants such as α, β, and with high infection rates and increased breakthroughs,resulting in vaccine inefficiencies and resistance to therapeutic monoclonal antibodies. Itremains urgentto identify novel therapeutics against broad strains of SARS-CoV-2 andfuture emerging corona viruses to protect the immune-compromised, unvaccinated, and even vaccinatedalikefrom evolvinginfectious diseases. Onebig question is whether we can harness power from human antiviral immunity for such broad therapeutic development. Wild-type SARS-CoV-2 and its variants infect human and other host cellsvia the entry receptor angiotensin-converting enzyme 2 (ACE2),triggeringinnate and adaptive immune responses. Herein, we reportan increase in circulating extracellular vesicles (EVs) that express ACE2(evACE2)in plasma ofboth acuteand convalescent COVID-19 patientsas part of innate antiviral responseassociatedwith severe pathogenesis. Furthermore, evACE2 isolated from both human plasma and engineered EV-producing cell lines neutralizes SARS-CoV-2 infection by competingwith cellular ACE2.Notably,evACE2 blocksthe binding of the viral spike (S)protein RBD to ACE2+cells ata135-fold higherpotencythan vesicle-free recombinant human ACE2 (rhACE2). Furthermore, evACE2 preventscellinfections by both pseudotyped and authentic SARS-CoV-2at a 60-to 80-fold higher efficacy than rhACE2; and itprotectsthe hACE2 mice from SARS-CoV-2-induced lung injury and mortality. More importantly, evACE2 inhibitsthe infection of SARS-CoV-2 variants (α, β,and δ)with an equal or even higherpotencythan forthe WT strain, supportingevACE2 as a broad-spectrum antiviral mechanismfor therapeutic developmentto block the infection of existing and future coronaviruses that use ACE2 as a receptor.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Huiping Liu 

PROVIDER: PXD029662 | JPOST Repository | Fri Dec 10 00:00:00 GMT 2021

REPOSITORIES: jPOST