The importance of autophagy in the fight against SARS-CoV-2 infections

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A review published by a researcher, Dr Theo Rein from the Max Planck Institute of Psychiatry, Munich-Germany in the peer reviewed Journal of Cellular Biochemistry highlights the importance of autophagy in the fight against SARS-CoV-2 infections and also identifies potential drugs that could be repurposed to treat COVID-19.

https://onlinelibrary.wiley.com/doi/10.1002/jcb.30166


AUTOPHAGY

In general, autophagy is an evolutionary conserved intracellular degradation process pivotal for cellular protein, energy, and organelle homeostasis.7 It is active under the basic condition at a low level ensuring continuous turnover and can be activated under certain stress conditions such as proteotoxicity or starvation.8 Material destined for degradation or recycling is engulfed by or transported into a double-membrane structure called “autophagosome.”

Through additional membrane remodeling processes, these autophagosomes fuse with lysosomes producing autolysosomes, with prior fusion with late endosomes as a potential intermediate step.9 As detailed in excellent reviews, this process is tightly controlled and executed by a vast array of proteins, ATG proteins in particular, but also EPG proteins required for the more complex autophagy in multicellular organisms.7-11

Autophagic flux refers to the activity through all consecutive steps of autophagy and typically is defined as a measure of autophagic degradation activity.12 Analytical tools assessing autophagic flux need to be chosen with great care to avoid erroneous conclusions.13

Several compounds currently are being developed, targeting different proteins in the autophagic cascade, given its involvement in various physiological and pathophysiological conditions, including viral infection.14, 15

AUTOPHAGY AND CORONAVIRUSES

The link between autophagy and invading pathogens is anything but new and both pro- and antiviral roles of autophagy were identified.16 For example, evidence suggests that double-membrane structures derived from the endoplasmic reticulum both are required for the initial steps of autophagy and serve as replication sites for coronaviruses17-22 (see also Figure 1).

Later on, several coronavirus proteins were shown to induce the formation of double-membrane structures, such as the nonstructural proteins 2, 3, 4, and 6.23 The broad activity against coronavirus replication of compounds that interfere with the generation of these structures further corroborates their importance.

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Figure 1 : Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication and endosomal/autophagic pathways, simplified scheme. Current knowledge supports both beneficial and detrimental effects of the autophagic pathway for SARS-CoV-2 replication. A major entry route for the virus is endocytic uptake, which requires lysosomal acidification for viral RNA release. The autophagic pathway is a multifactorial and multistep pathway with a vast range of possibilities for pharmacological targeting. In the more initial phases, phagophores, and double-membrane vesicles (DMVs) are formed, most likely from the endoplasmic reticulum, possibly also promoted by some coronavirus proteins. SARS-CoV-2 replication takes place at the endoplasmic reticulum as well, at very similar, if not identical, membrane structures. SARS-CoV-2 inhibits the last step of autophagy leading to viral degradation, that is, the fusion of autophagosomes with lysosomes to form autolysosomes, thus inhibiting autophagic flux. Accordingly, compounds impacting autophagy are expected to be efficient in fighting SARS-CoV-2 only if they enhance autophagic flux

In contrast to this appearing congruence of viral mechanisms and early steps of autophagy, there is also firm evidence that coronaviruses interfere with late steps of autophagy to evade degradation. Very recently, for example, ORF3a (the protein derived from open reading frame 3a) of SARS-CoV-2 has been demonstrated to inhibit the fusion of autophagosomes with lysosomes, thereby increasing the number of autophagosomes but decreasing autophagic flux,24, 25 in line with the effect of coronavirus infection.26, 27

However, the exact details of how coronaviruses in general, and SARS-CoV-2 in particular, are intertwined with autophagy await further elucidation.23, 28, 29 Nevertheless, it appears plausible that coronaviruses may benefit from earlier steps of the autophagic pathway, but are vulnerable to the increased autophagic flux that clears out viral particles. This is supported by reports showing that induction of autophagy has the potential to fight coronavirus infection.26, 27

Chloroquine inhibits autophagy by interfering with autophagosome-lysosome fusion.30 However, chloroquine and hydroxychloroquine exert additional effects like disorganizing the endo–lysosomal system that might have been the basis for the initial hope put on this drug for Covid-19 treatment.31, 32

However, with more studies coming up, no overall beneficial effect of this drug on Covid-19 was apparent,33-35 and the drug now is abandoned in the WHO Solidarity program. Therefore, it appears likely that autophagy-targeting drugs need to promote autophagy flux rather than other aspects of autophagy.

Although COVID-19 primarily is a respiratory disease, multiple organs are affected, either through cytokines or directly upon invasion of SARS-CoV-2.36-38

As autophagy is a conserved mechanism operative in most cells, pharmacological induction of autophagy has the potential to fight SARS-CoV-2 in all organs that are reached by the compound. However, the effect on overall health may depend on existing comorbidities, such as cancer, for example, where the effect of autophagy depends on the circumstances.39, 40


Repurposing existing approved drugs with known safety profile is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current COVID-19) pandemic.

The World Health Organization recently announced testing of three drugs (infliximab, imatinib, and artesunate in the Solidarity program) as potential COVID-19 therapeutics that are known for their dampening effect on the immune system.

Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle. https://europepmc.org/article/med/33963326

Despite widespread vaccination campaigns are currently in progress around the world in an effort to control the COVID-19 pandemic, emerging variants and sub-variants that are immune evasive are beginning to challenge the whole exercise.

Also, although vaccination poses an appreciable prophylactic measure to prevent SARS-CoV-2 infections, the scientific community is still struggling to develop a robust treatment to cure already infected COVID-19 patients.

While vaccines were rapidly developed and marketed with unprecedented swiftness, drug development has traditionally been much more time extensive.

Taking into account the acute urgency, drug repurposing has emerged as a promising strategy that is already being followed or tested in several preclinical and clinical trials.

In this current Autophagy-SARS-CoV-2 review, German researcher Dr Theo Rein discusses autophagy as a potential contributing mechanism of selected drugs that are currently being evaluated under the World Health Organization (WHO) Solidarity program in the treatment of COVID‐19.

The word autophagy is derived from Greek words “auto” meaning self and “phagy” meaning eating. Autophagy is a normal physiological process in the body that deals with destruction of cells in the body. Autophagy is an evolutionarily conserved intracellular self-degradative process that plays a crucial housekeeping role in removing misfolded proteins, clearing damaged organelles, as well as eliminating intracellular pathogens, including viruses.

It has been found that during autophagy, cellular elements destined for degradation are engulfed by a double‐membrane structure called an autophagosome. These autophagosomes eventually fuse with lysosomes producing autolysosomes, where degradation takes place. The rate of autophagic degradation through this degradative cascade is known as “autophagic flux.”

The whole entire process of autophagy is tightly controlled and executed by a vast array of proteins.  Given its involvement in various pathological conditions including viral infection, scientists across the world are trying to develop drug compounds that target proteins in the autophagic cascade.

Interestingly double‐membrane structures derived from the endoplasmic reticulum, which are typically required for the initial steps of autophagy, are contrived to serve as replication sites by coronaviruses. In addition, non-structural proteins of coronaviruses induce the formation of these double‐membrane structures. 

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060226

https://pubmed.ncbi.nlm.nih.gov/18725538/

https://www.jbc.org/article/S0021-9258(17)47665-4/fulltext

https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(10)00176-9

https://pubmed.ncbi.nlm.nih.gov/20088951/

https://pubmed.ncbi.nlm.nih.gov/21799305/

Aside from maneuvering early steps, coronaviruses can also interfere with the late steps of autophagy to evade degradation. Regarding SARS-CoV-2, the ORF3a protein has recently been reported to inhibit the fusion of autophagosomes with lysosomes. As a result, ORF3a increases autophagosomes but decreases autophagic flux, thus providing an escape from autophagy. 

https://pubmed.ncbi.nlm.nih.gov/33422265/

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