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Canonical and Noncanonical Autophagy as Potential Targets for COVID-19.

ABSTRACT: The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection.

SUBMITTER: Bello-Perez M

PROVIDER: S-EPMC7408018 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Canonical and Noncanonical Autophagy as Potential Targets for COVID-19.

Bello-Perez Melissa M Sola Isabel I Novoa Beatriz B Klionsky Daniel J DJ Falco Alberto A

Cells 20200705 7

The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellu ...[more]

PMID: 32635598

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Project description:The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren's syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still's disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.Key Points• Patients with coronavirus disease 19 (COVID-19) may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, thrombocytopenia and cytokine storm with features akin to secondary hemophagocytic lymphohistiocytosis.• Although preliminary results may be encouraging, high-quality clinical trials are needed to better understand the role of drugs commonly used in rheumatology like hydroxychloroquine and tocilizumab in COVID-19.• Until further evidence emerges, it may be cautiously recommended to continue glucocorticoids and other disease-modifying antirheumatic drugs (DMARDs) in patients receiving these therapies, with discontinuation of DMARDs during infections as per standard practice.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-α subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.

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Canonical and Noncanonical Autophagy as Potential Targets for COVID-19.

Publications

Canonical and Noncanonical Autophagy as Potential Targets for COVID-19.

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