Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics
autophagy/lysosome drug discovery/repurposing therapeutics virology
Authors: Gassen et al. Link to paper: https://www.biorxiv.org/content/10.1101/2020.04.15.997254v1
Journal/ Pre-Print: BioRxiv
Key Words: Autophagy, Drug Repurpose, Anti-viral, In vitro, Pre-clinical
1. Autophagy is decreased in SARS-CoV2 infected cells
2. Viral replication leads to increase of glycolytic pathways and blocks conversion of putrescine to spermidine
3. (Pre-)Treatment of cells with autophagy-inducing agents reduces viral replication
Our knowledge of the molecular changes induced by SARS-CoV2 upon viral entry remain largely unknown. This study directly shows the impact the virus has on cellular autophagic machinery. The authors could show that autophagy is reduced in infected in vitro cell lines through changes in activation states of crucial autophagy-related genes. Furthermore, they could identify aberrant metabolic pathways due to the viral infection and finally show that using agents (e.g. MK-2206) and supplementation (e.g. spermidine) can maintain autophagic flux and reduce viral replication/output. Overall, the study provides an interesting novel molecular target to reduce viral replication, potentially through regulation of autophagy.
IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS
Understand the virology and/or cell biology of SARS-CoV2/COVID19
The paper identifies the consequences of SARS-CoV2 infection in cell line models and its effect on cellular autophagy levels. It further shows metabolic changes underlying active viral replication.
Inhibit of SARS-CoV2/COVID19 transmission
The paper uses also autophagy modulators and could show that some of them are capable to reduce viral loads produced, which is a possible way to reduce viral transmission.
· In vitro study
STRENGTHS AND LIMITATIONS OF THE PAPER
Novelty: The study provides novel insights into the cellular biology of SARS-CoV2 infected cells both from a metabolic as well as autophagic perspective. The degree of novelty may be arguable as similar observations have been previously done with SARS-CoV.
Standing in the field: The data is supported by previous reports (of the same main authors, Gassen et al. 2019 Nat Comms) showing similar alterations and therapeutic effects of modulators of autophagy in SARS-CoV infected cells. Virus are generally known to change autophagic flux by modulating the activity of several autophagy regulated genes (see Choi, Bowman and Jung, Nat Rev Microbiology, 2018).
Appropriate statistics: Appropriate statistics
Viral model used: SARS-CoV2 (Munich strain)
Translatability: The data shown here have a potential to be translated into clinical trials. The study provides only pre-clinical results. However, all proposed drugs have been in clinical trials before and therefore have been shown to be safe in Phase I clinical trials. This may speed up potential Phase II clinical trials.
Main limitations: The study was overall well conducted. Our main criticism is that the authors missed to provide conclusive evidence that the effect of their drugs is mediated through upregulation of autophagy (using a KO model they could have provided this proof). Further, the authors could have investigated the effects of spermidine decrease in SARS-CoV2 cells on TFEB hypusination and regulation of autophagy.
Lastly, it would have been interesting to see similar data obtained in infected primary cells due to possible metabolic and cellular differences between immortalized cell lines and primary cells.