Taming the Autophagy as a Strategy for Treating COVID-19

Abstract

Currently, an efficient treatment for COVID-19 is still unavailable, and people are continuing to die from complications associated with SARS-CoV-2 infection. Thus, the development of new therapeutic approaches is urgently needed, and one alternative is to target the mechanisms of autophagy. Due to its multifaceted role in physiological processes, many questions remain unanswered about the possible advantages of inhibiting or activating autophagy. Based on a search of the literature in this field, a novel analysis has been made to highlight the relation between the mechanisms of autophagy in antiviral and inflammatory activity in contrast with those of the pathogenesis of COVID-19. The present analysis reveals a remarkable coincidence between the uncontrolled inflammation triggered by SARS-CoV-2 and autophagy defects. Particularly, there is conclusive evidence about the substantial contribution of two concomitant factors to the development of severe COVID-19: a delayed or absent type I and III interferon (IFN-I and IFN-III) response together with robust cytokine and chemokine production. In addition, a negative interplay exists between autophagy and an IFN-I response. According to previous studies, the clinical decision to inhibit or activate autophagy should depend on the underlying context of the pathological timeline of COVID-19. Several treatment options are herein discussed as a guide for future research on this topic.

Keywords: COVID-19; SARS-CoV-2; autophagy; cytokine storm; inflammation; obesity.

Figure 1

Schematic coronaviruses-autophagy relationship. The figure shows the main findings related to the inhibition or triggering of autophagy by coronaviruses. Green lines represent the complete activation of autophagy by coronaviruses. Red lines show inhibition of autophagy or incomplete autophagy. Blue line indicates the double-membrane vesicles (DMVs) formation by coronaviruses independent of autophagy. In some cellular models, SARS-CoV and mouse hepatitis virus (MHV) exploit the non-lipidated form of LC3 and its replication is independent of autophagy.

Figure 2

Negative regulation of interferons (IFNs) by autophagy. Upon recognition of viral pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), several signaling pathways are activated to produce IFNs. This response is amplified by the activation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. Some coronaviruses negatively regulate the IFNs’ response via the autophagic degradation of key molecules downstream of IFN signaling cascade (e.g., IRF3, MAVS, NLRX1, mitochondria, MyD88 and STAT).

Figure 3

Regulation of inflammation by autophagy. The principal points downstream of proinflammatory cytokine signaling that can be potentially regulated by autophagy are indicated. The proinflammatory response might be regulated by autophagic degradation of pivotal molecules like MyD88, the nuclear factor kB (NF-κB) and depolarized mitochondria and ROS. Moreover, autophagy can regulate IL-1β production via the removal of ASC pyroptosome, pro-caspase 1 and pro-IL-1.

Figure 4

Main action mechanisms of chloroquine (CQ) and hydroxychloroquine (HCQ) related to antiviral and immunomodulators properties. By increasing the pH into lysosomes, CQ and HCQ interfere with cargo derived from endocytosis and/or from autophagic pathway. Moreover, CQ and HCQ prevent the PAMPs’ recognition by Toll-like receptors (TLRs). These drugs can inhibit the TLR and STING signaling, which automatically decreases the production of pro-inflammatory cytokines including the IFN response.

Figure 5

Schematic proposal to modulate autophagy in the context of the pathological timeline of COVID-19. Pharmacological inhibition of the autophagy at the first stage might regulate the IFN antiviral responses and restrict viral replication. Activation of autophagy at the third stage could contribute to the elimination of reactive molecules as ROS, to the removal of damaged organelles to decrease the inflammation and to restoring the balance of the immune response.