Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity
bioinformatics immunology/immunity inflammation
Authors: Saichi et al.
Link to paper: https://www.biorxiv.org/content/10.1101/2020.07.20.212837v1
Journal/ Pre-Print: BioRxiv
Tags: Immunology/Immunity, Inflammation, Bioinformatics
Single-cell RNA sequencing analysis of antigen-presenting cells from the PBMCs of COVID-19 patients revealed an increase in inflammation-associated pathways and a defective cytokine and IFN response.
Multiple processes in anti-viral immunity have been revealed to be defective in specific APC subsets, including apoptosis, innate sensing receptors, Interferon stimulated genes (ISG) and antigen presentation.
In this study, the authors analyse single-cell RNA sequencing (scRNA-seq) data from antigen-presenting cell (APC)-enriched peripheral blood mononuclear cells (PBMCs) of seven COVID-19 patients, with either moderate or severe disease, taken 1- and 4-days post-hospital admission and of healthy controls. Analysis of differentially expressed genes (DEG) between severity groups revealed alterations in APC subset distribution, inflammatory cytokine and IFN responses, apoptosis, p53 pathway, IL6/JAK/STAT3 signaling, IL2/STAT5 signaling, transcription, MHC-II related genes and MHC-II transactivator activity. Some of these defects showed cell type specificity and correlated with disease severity. Moreover, multi-process defects were found persistent on day-4 post-admission in severe COVID-19 APC subsets compared to those taken on day 1. Together, these results provide a molecular map of DC subsets and their underlying molecular pathways in the context of COVID-19.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
In silico study / bioinformatics study
Patient case study
Strengths and Limitations of the Paper
Novelty: The authors used APC-enriched PBMCs and focused their analysis on DC subsets including rare pDC, AS-DC and CLEC9A+ DC.
Standing in the field: Other studies have also shown an impaired type I IFN response in severe COVID-19. Their findings on interferon-stimulated gene, HLA class II downregulation and pro-inflammatory cytokines are consistent with a paper published earlier this year:
Wilk, A. J. et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 26, 1070–1076 (2020).
Appropriate statistics: Adequate
Viral model used: SARS-CoV-2
Translatability: Not directly translatable. However, it could partially explain why some patients are more affected by COVID-19 than others and provides valuable insight for the development of novel therapies to restore APC functions.
Sample size, particularly by disease severity, is limited
Based on their UMAP plots, the authors could have subclustered their samples further to achieve higher-resolution maps to better explore differences between their patient groups; given the cluster distribution, there are cells that appear to be patient group-specific but this is not investigated as detailed subclustering is not performed and compositional differences are not assessed (potentially due to the DC enrichment strategy).
Certain QC filtering thresholds appear to be a bit less stringent than one might anticipate (eg excluding cells with <50 expressed genes and >50% mitochondrial transcripts)
Data on moderate COVID-19 were from hospitalised patients. It would have been nice to compare the response to SARS-CoV-2-infected individuals who did not require hospital admission or develop pneumonia.