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

Figures & data

Figure 1. Modulation of the autophagy pathway by coronaviruses and proposal of novel smart drug-loaded nanoparticles to target this pathway to combat COVID-19. Schematic shows how coronaviruses interact with autophagy. The NSP6 protein of SARS and MHV induces the formation of autophagosomes but confines their expansion and blocks their maturation into autolysosomes. A similar effect is observed by PLpro-TM of SARS. Human CoVs (HCoVs) via their NSPs, and MHV induce the formation of LC3-I-coated DMVs needed for viral RNA transcription and replication. MERS decreases the level of BECN1 (beclin 1) and blocks fusion of autophagosomes with lysosomes. Chloroquine/hydroxychloroquine, emtricitabine/tenofovir, interferon alfa-2b, lopinavir/ritonavir and ruxolitinib, which are all under clinical trial for treatment of SARS-CoV-2, induce autophagosome accumulation by blocking their maturation into autolysosomes. Thus, designing nanoparticles for the targeted delivery of these drug to avoid their off-target effects will provide safe and effective powerful tools to combat COVID-19. ATG14: autophagy related 14; DMV: double-membrane vesicles; EDEMosome: LC3-I-positive endoplasmic reticulum-derived vesicles exporting short-lived ERAD regulators; ER: endoplasmic reticulum; LC3-I: processed MAP1LC3; LC3-II: lipidated MAP1LC3; MERS: Middle East respiratory syndrome; MHV: murine gammaherpes virus; NSP6: non-structural protein 6; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3 K: class III phosphatidylinositol 3-kinase; PLpro-TM: membrane-anchored papain-like protease; SARS: severe acute respiratory syndrome; ULK1 complex: unc-51 like autophagy activating kinase 1.

Table 1. Drugs under clinical trials against SARS-CoV-2 infection based on the World Health Organization report [19], their autophagy-related mechanism of action, and their severe side-effects.

Drug Name	Autophagy-related mechanism of action	Side effects
CQ/HCQ	Inhibits autophagy flux by decreasing autophagosome-lysosome fusion [40]	Retinopathy, gastrointestinal effects, cardiomyopathy, myopathy [41]
Corticosteroids	Inhibits autophagy by blocking LC3 recruitment [42]	Myopathy, osteopenia/osteoporosis, decreased sex hormones [43]
Emtricitabine/Tenofovir	Increases expression and accumulation of SQSTM1/p62 [44], decreases fusion of autophagosomes with lysosomes [45]	Renal toxicity [46]
Interferon alfa-2b	Induces autophagy and accumulation of autolysosomes [47]	Flu-like symptoms, nausea, anorexia, depression, confusion, myalgia, fatigue, joint pain [25] retinopathy, neuropsychopathy [48]
Lopinavir/Ritonavir	Induces autophagosome accumulation [49]	Gastrointestinal effects, headache, diabetes, hyperbilirubinemia, dizziness [50]
Ruxolitinib	Downregulates the MTORC1-RPS6KB-EIF4EBP1 pathway [51], induces accumulation of autophagosomes [52]	Anemia, pancytopenia [53]

EIF4EBP1: eukaryotic translation initiation factor 4E binding protein I; LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; RPS6KB/p70S6K: ribosomal protein S6 kinase B; SQSTM1/p62: sequestosome 1

Table

ATG5	autophagy related 5
βCoV	betacoronavirus
DMVs	double-membrane vesicles
HIV-1	human immunodeficiency virus - I
MAP1LC3/LC3	microtubule associated protein 1 light chain 3
MERS-CoV	Middle East respiratory syndrome-coronavirus
MHV	murine gammaherpesvirus
NSP6	non-structural protein 6
SARS-CoV	severe acute respiratory syndrome-coronavirus
SARS-CoV-2	severe acute respiratory syndrome-coronavirus 2
UPR	unfolded protein response
WHO	World Health Organization

WHO; 2020. Table of therapeutics against COVID-19 as 21st March 2020 WHO. Available from: https://www.who.int/blueprint/priority-diseases/key-action/Table_of_therapeutics_Appendix_17022020.pdf?ua=1

 Google Scholar

Mauthe M, Orhon I, Rocchi C, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435–1455.

 PubMed Web of Science ®Google Scholar

Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155–166.

 PubMed Web of Science ®Google Scholar

Kyrmizi I, Gresnigt MS, Akoumianaki T, et al. Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling. J Immunol. 2013;191(3):1287–1299.

 PubMed Web of Science ®Google Scholar

Langhammer A, Forsmo S, Syversen U. Long-term therapy in COPD: any evidence of adverse effect on bone? Int J Chron Obstruct Pulmon Dis. 2009;4:365–380.

 PubMedGoogle Scholar

Rodriguez M, Lapierre J, Ojha CR, et al. Morphine counteracts the antiviral effect of antiretroviral drugs and causes upregulation of p62/SQSTM1 and histone-modifying enzymes in HIV-infected astrocytes. J Neurovirol. 2019;25(2):263–274.

 PubMed Web of Science ®Google Scholar

Tripathi A, Thangaraj A, Chivero ET, et al. Antiretroviral-mediated microglial activation involves dysregulated autophagy and lysosomal dysfunction. Cells. 2019;8(10):1168.

 Web of Science ®Google Scholar

Stravitz RT, Shiffman ML, Kimmel M, et al. Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation. Liver Int. 2012;32(7):1138–1145.

 PubMed Web of Science ®Google Scholar

Zhao J, Wang ML, Li Z, et al. Interferon-alpha-2b induces autophagy in hepatocellular carcinoma cells through Beclin1 pathway. Cancer Biol Med. 2014;11(1):64–68.

 PubMedGoogle Scholar

Pestka S. The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem. 2007;282(28):20047–20051.

 PubMed Web of Science ®Google Scholar

Hejny C, Sternberg P, Lawson DH, et al. Retinopathy associated with high-dose interferon alfa-2b therapy. Am J Ophthalmol. 2001;131(6):782–787.

 PubMed Web of Science ®Google Scholar

Zha BS, Wan X, Zhang X, et al. HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes. PLoS One. 2013;8(3):e59514.

 PubMed Web of Science ®Google Scholar

Kim MJ, Kim SW, Chang HH, et al. Comparison of antiretroviral regimens: adverse effects and tolerability failure that cause regimen switching. Infect Chemother. 2015;47(4):231–238.

 PubMed Web of Science ®Google Scholar

Ishida S, Akiyama H, Umezawa Y, et al. Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2. Oncotarget. 2018;9(42):26834–26851.

 PubMedGoogle Scholar

Kusoglu A, Bagca BG, Ozates Ay NP, et al. Ruxolitinib regulates the autophagy machinery in multiple myeloma cells. Anticancer Agents Med Chem. 2020;20. DOI:https://doi.org/10.2174/1871520620666200218105159

 Google Scholar

Alimam S, McLornan D, Harrison C. The use of JAK inhibitors for low-risk myelofibrosis. Expert Rev Hematol. 2015;8(5):551–553.

 PubMed Web of Science ®Google Scholar