Autophagy and SARS-CoV-2 infection: A possible smart targeting of the autophagy pathway

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in 5,993,317 confirmed cases worldwide with 365,394 confirmed deaths (as of May 29 th , 2020, WHO). The molecular mechanism of virus infection and spread in the body is not yet disclosed, but studies on other betacoronaviruses show that, upon cell infection, these viruses inhibit macroautophagy/autophagy flux and cause the accumulation of autophagosomes. No drug has yet been approved for the treatment of SARS-CoV-2 infection; however, preclinical investigations suggested repurposing of several FDA-approved drugs for clinical trials. Half of these drugs are modulators of the autophagy pathway. Unexpectedly, instead of acting by directly antagonizing the effects of viruses, these drugs appear to function by suppressing autophagy flux. Based on the established cross-talk between autophagy and apoptosis, we speculate that over-accumulation of autophagosomes activates an apoptotic pathway that results in apoptotic death of the infected cells and disrupts the virus replication cycle. However, administration of the suggested drugs are associated with severe adverse effects due to their off-target accumulation. Nanoparticle targeting of autophagy at the sites of interest could be a powerful tool to efficiently overcome SARS-CoV-2 infection while avoiding the common adverse effects of these drugs.

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19

“…Protective environment of DMVs or autophagosomes concealing viral RNA is formed by the attachment of RTC with membrane derived from ER ( Blanchard and Roingeard, 2015 ; Knoops et al, 2008 ), enabling it to escape the dsRNA-triggered host antiviral response ( Astuti, 2020 ; Kumar et al, 2020 ; Margaritopoulos et al, 2017 ). SARS-CoV-2 escapes autophagy by inhibiting the activation of AMP-protein activated kinase (AMPK), and by promoting the mammalian activation target of rapamycin complex 1 (mTORC1) ( Shojaei et al, 2020 ; Wong and Sanyal, 2020 ). Nitazoxanide promotes autophagy leading to degradation of DMVs contents by activating AMPK and inhibiting mTORC1, thereby adversely affecting virus genome synthesis ( Fig.…”

Statins in Patients with COVID-19: A Retrospective Cohort Study in Iranian COVID-19 Patients

“…Autophagy is an important cellular mechanism against different types of stress, including viral infection [3,63,64]. SARS-CoV-2 infection likely changes autophagy ux in the infected cells and hijacks it for its replication [3]. The clinical effects of statins described to date have in part been attributed to their impact on the cellular autophagy pathway.…”

“…The novel coronavirus, SARS-CoV-2, causing coronavirus disease 2019 (COVID-19) is a major health threat that was declared a global pandemic by the World Health Organization (WHO) in March 2020 [1][2][3]. Since the outbreak in December 2019, many people have suffered from a severe acute respiratory infection that causes respiratory failure, the need for intubation, and prolonged mechanical ventilation [4].…”

Emerging Molecular Prospective of SARS-CoV-2: Feasible Nanotechnology Based Detection and Inhibition

“…Although the ORF-8b of SARS-CoV has less homology with that of SARS-CoV-2, the maturation of viral proteins occurring inside the ER might increase the workload, causing ER stress and subsequent apoptosis (Fung et al, 2020). Furthermore, the PERK and IRE1 signaling pathways are common to both the cellular events of ER stress and autophagy, which justify that these processes are inter-connected via the UPR system (Shojaei et al, 2020). The accumulated unfolded and misfolded proteins subsequently increase ER stress and, to combat it, the cytosolic ubiquitin-proteasomes level increases (Boga and Coto-Montes, 2020).…”