Engineered extracellular vesicles antagonize SARS-CoV-2 infection by inhibiting mTOR signaling

Abstract

Effective treatment approaches for patients with COVID-19 remain limited and are neither curative nor widely applicable. Activated specialized tissue effector extracellular vesicles (ASTEX) derived from genetically-enhanced skin fibroblasts, exert disease-modifying bioactivity in vivo in models of heart disease. Here we report that ASTEX antagonizes SARS-CoV-2 infection and its pathogenic sequelae: In human lung epithelial cells exposed to SARS-CoV-2, ASTEX is cytoprotective and antiviral biologics. Transcriptomic analysis implicated the mammalian target of rapamycin (mTOR) pathway, as infected cells upregulated mTOR signaling and pre-exposure to ASTEX attenuated it. The implication of mTOR signaling was further confirmed using mTOR inhibition and activation, which increased and decreased viral load, respectively. Dissection of ASTEX cargo identifies miR-10a and miR-16 as potential EV inhibitors of mTOR signaling. The findings reveal a novel, dual mechanism of action for ASTEX as a therapeutic candidate for COVID-19, with synergistic antiviral and cytoprotective benefits.

Post-acute Sequelae in COVID-19 Survivors: an Overview

“…Clinical trials of antifibrotic therapies to limit/prevent pulmonary fibrosis for post-COVID patients are currently in progress; however, lung transplantations may be performed for fibroproliferative lung disease after ARDS due to COVID-19 [13]. ASTEX (activated specialized tissue effector extracellular) vesicles are cytoprotective and antiviral in human lung epithelial cells subjected to SARS-CoV-2 [66][67][68]. It inhibits SARS-CoV-2 infection and its pathogenic consequences by suppressing mTOR signaling, which in turn alters the transcriptome of infected cells [66][67][68].…”

“…ASTEX (activated specialized tissue effector extracellular) vesicles are cytoprotective and antiviral in human lung epithelial cells subjected to SARS-CoV-2 [66][67][68]. It inhibits SARS-CoV-2 infection and its pathogenic consequences by suppressing mTOR signaling, which in turn alters the transcriptome of infected cells [66][67][68].…”

The regulation of skin homeostasis, repair and the pathogenesis of skin diseases by spatiotemporal activation of epidermal mTOR signaling

“…Furthermore, it has been shown that COVID-19 infected patient tissues and epithelial cells exhibit the abnormally activated mTOR signaling pathway, as evidenced by increased levels of phosphorylated 4E-BP1, AKT, S6K1 and mTOR (Appelberg et al, 2020;Mullen et al, 2021), suggesting the relevance of mTOR signaling activity and SARS-CoV-2 infection. More importantly, small molecule inhibitors targeting AKT and mTOR and engineered extracellular vesicles encapsulated microRNA targeting mTOR are able to significantly antagonize SARS-CoV-2 infection (Ibrahim et al, 2022), highlighting that inhibition of mTOR represents a feasible strategy for preventing COVID-19 (Basile et al, 2022).…”

The Potential Role of Growth Differentiation Factor 15 in COVID-19: A Corollary Subjective Effect or Not?

“…Moreover, the mechanistic target of the rapamycin (mTOR) pathway is the innermost regulator of cell growth, proliferation, metabolism and survival [ 54 ]. This pathway is a member of the protein kinases that senses both extracellular and intracellular regulatory signals to manage autophagy, the expression of inflammatory genes and organelle biogenesis [ 54 ].…”

“…Moreover, the mechanistic target of the rapamycin (mTOR) pathway is the innermost regulator of cell growth, proliferation, metabolism and survival [ 54 ]. This pathway is a member of the protein kinases that senses both extracellular and intracellular regulatory signals to manage autophagy, the expression of inflammatory genes and organelle biogenesis [ 54 ]. It has been shown that the mTOR pathway is activated during the SARS-CoV-2 infection, and involved in the transcription and mRNA translation of the SARS-CoV-2 particles [ 55 ].…”