4.3. Critical Role of Autophagy in COVID-19 Exacerbations
The ongoing SARS-CoV-2 pandemic has severely impacted quality of life with a significant health care and socio-economic burden globally. In general, the cellular endocytic and autophagy pathways contribute to viral entry and replication, and thus are obvious attractive targets against SARS-CoV-2 and other viral infections [90,91,92]. The SARS-CoV-2 virus, which causes COVID-19, is highly infectious and can cause cytokine-storm leading to pneumonia and severe lung damage in susceptible subjects by triggering an ARDS-like lung disease, with high-risk of mortality [135]. Recent evidence suggests that SARS-CoV-2 may inhibit autophagy, which we anticipate as a potential mechanism for severe COVID-19 lung disease due to impaired viral clearance and immune dysfunction. In a recent study of the SARS-CoV-2 genome, researchers found that the NSP6 protein of the virus binds with greater affinity to the endoplasmic reticulum (ER) [136]. This genetic change may allow the virus to inhibit autophagy via impaired autophagosome processing, which prevents the degradation of viral particles by the lysosome [136]. There is also evidence that PLP2 is over-expressed in SARS-CoV and MERS-CoV cell lines that also allows the virus to inhibit autophagolysosomal formation and autophagy flux and is likely a method of autophagy inhibition in SARS-CoV-2 [96]. These studies suggest potential mechanism by which SARS-CoV-2 inhibits autophagy to infect or circumvent host cells pathogenic clearance pathways and limit an adequate immune response similar to other coronaviruses that warrants further investigation.
The elimination of viruses by autophagy (sometimes termed as virophagy) has been well described for a variety of viral infections [8,84,85,137]. Although, the virus has multiple ways of entry into the cell, autophagy augmentation provides strategic advantage in reducing viral load by promoting its clearance [90,137]. As a proof of concept, recent study demonstrated the utility of three different autophagy-inducing drugs, spermidine, MK02206, and niclosamide, in restricting SARS-CoV-2 propagation [138]. Autophagy induction and related upregulation of overall immunity helps combat exacerbations and is suggested as an immunity boosting strategy as a preventive measure against COVID-19 [139]. In addition to boosting immunity, dampening viral load, and allowing SARS-COV2 clearance, autophagy induction may provide strategic advantage in the treatment of COVID-19 and prevention of negative outcomes, which makes it a subject of ongoing studies. In support of this, autophagy inhibiting drugs, such as hydroxychloroquine (HCQ) that help dampen the immune response in rheumatoid arthritis, malaria, and other illnesses but weakens cellular ability for viral clearance by the critical homeostatic process autophagy. Despite early claims that HCQ may provide benefit in treating COVID-19 [90,91,92], it has since been deemed unsafe for use in COVID-19 treatment by the FDA based on randomized double blind placebo control trials [140,141]. In addition, earlier studies on Middle East respiratory syndrome (MERS) coronavirus [50] provide proof-of-concept data on therapeutic potential of autophagy modulating drugs to combat SARS-COV2 infection, cytokine storm, and the pathogenesis of severe ARDS-like COVID-19 fatal lung disease. Prior studies showing a protective role of autophagy induction in other models of ARDS demonstrate the scope of autophagy augmenting strategies in combating SARS-CoV-2 infections (Figure 1) and thus is part of ongoing validation and rapid clinical development studies that may help limit the burden and spread of this novel virus.
As discussed above for other lung diseases, targeting autophagy to prevent the replication of SARS-CoV-2 is not the only potential benefit of autophagy augmentation for the treatment of COVID-19, but it may also allow the fine-tuning of optimal inflammatory responses. As now known, the pathogenesis of SARS-CoV-2-mediated severe COVID-19 involves the activation of numerous pro-inflammatory cytokines as part of the aforementioned cytokine storm causing a hyper-inflammatory state [142]. In addition to the destruction of the lungs and ARDS associated with COVID-19, this inflammatory response can cause damage to the cardiovascular, nervous, renal, hepatic, and gastrointestinal systems with wide ranging immediate and long-term consequences [142]. In support of this, studies have demonstrated the role of autophagy in the inflammatory response within the lungs and other organ systems [61]. As mentioned above, autophagy induction has been demonstrated to attenuate lung inflammation when exposed to a pathogen. Thus, autophagy induction to limit the inflammatory response, in addition to infection, has an immense therapeutic potential as an effective treatment for COVID-19 and decreasing the associated mortality and morbidity.