Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection

Authors: Singh et al

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.13.092536v1

Journal/ Pre-Print: BioRxiv

Tags: Autophagy/Lysosomes, Bioinformatics, Inflammation 

Research Highlights

1. SARS-CoV-2 infection in lung epithelial cells results in changes in autophagy, mitochondrial respiration and inflammatory genes

2. MERS-CoV and SARS-CoV-2 infection share alterations in autophagy and mitochondrial pathways, but inflammatory nodes are specific to SARS-CoV-2

Summary 

This study investigates the cellular networks that are altered during SARS-CoV-2 infection in lung epithelial cells. Specifically, the authors use publicly available datasets of SARS-CoV-2, MERS-CoV or Influenza A infection in A549 or Calu3 cells, a COVID-19 patient lung transcriptome and a single cell RNA-seq dataset of human lung cells. The study elucidates changes in the mitochondrial and autophagy pathways, which are shared between SARS-CoV-2 and MERS-CoV infection. However, the authors find that only SARS-CoV-2 infection results in a strong inflammatory gene signature. The identified pathway dysregulations from this and other investigations can provide important hints into potential therapeutic targets.

Impact for SARS-CoV2/COVID19 research efforts

Understand the virology and/or cell biology of SARS-CoV2/COVID19: Bioinformatic analysis to identify modules associated with SARS-CoV-2 infection in human lung cell lines.

Study Type

· In silico study / bioinformatics study

Strengths and limitations of the paper

Novelty: This study is novel in that it combines multiple pre-existing datasets to understand cellular pathways that are dysregulated in SARS-CoV-2 infection. Interestingly, the autophagy pathway genes are up- or down-regulated in this article, which could hint at at sevral new hypotheses: (1) SARS-CoV-2 using autophagosomal membranes as niches for replication; (2) autophagy limiting the inflammatory response; (3) autophagy maintaining mitochondrial integrity

Standing in the field: The authors show that the autophagy pathway is affected in SARS-CoV-2 infection of lung epithelial cell lines. Autophagy induction has been shown to limit SARS-CoV-2 spread in vitro (Gassen et al, BioRxiv, 2020). At the same time, mTOR signalling, which counters autophagy and oxidative phosphorylation, has been implicated in SARS-CoV-2 infected cells (Appelberg et al, BioRxiv, 2020).

Appropriate statistics: Yes

Viral model used: Used data from other studies (USA-WA1/2020 SARS-CoV-2 strain)

Translatability: Not very translatable

Main limitations:

1. The methods are not well described and WGCNA parameters used are not specified

2. Discussion on how altering mitochondrial processes might be impacting immune cell function is lacking

3. Supplementary figures not accessible (while supplementary tables are), so could not be evaluated

4. The authors relate ACE2 overexpression to high titer infection, but do not explain whether viral titers found in COVID-19 lungs are similar

5. The study primarily relies upon immortalized cell lines and it would be useful to evaluate how these findings translate into primary cells