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Authors: Schulte-Schrepping et al

Link to paper: https://www.medrxiv.org/content/10.1101/2020.06.03.20119818v1

Journal/ Pre-Print: MedRxiv

Tags: Immunology/Immunity, Inflammation, Bioinformatics

Research Highlights

1. Mild COVID-19 patients seem to have a strong interferon-stimulated gene signature in blood HLA-DRhiCD11chi monocytes at early disease stages, which is not present to the same extent in severe disease.

2. Low density neutrophils (LDNs) were found in PBMCs of Covid-19 patients by CyTOF and scRNAseq, consisting of a heterogeneous population of activated or immature neutrophils.

3. The neutrophils from Covid-19 patients show upregulated expression of genes that have been associated to acute inflammation and/or immunosuppression.

Summary

The study by Schulte-Schrepping et al comprehensively explores blood myeloid cells of mild and severe COVID-19 patients. The authors use a combination of single cell RNAseq, CyTOF and flow cytometry and particularly focus on monocytes and neutrophils. HLA-DRhiCD11chi monocytes from patients with mild COVID-19 seem to have an early and robust interferon-stimulated gene signature, which was not observed to the same extent in severe disease. Severe COVID-19 patients seem to have an enhanced HLA-DRlo, suppressive monocyte signature. Importantly, the authors found low-density and immature neutrophils in severe COVID-19 patients. This dataset can act as a valuable resource to delineate the innate immune dysregulation in COVID-19.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19: the authors examine immune cell subset changes during disease.

Study Type

· Patient Case study

Strengths and limitations of the paper

Novelty: Repeated sampling of multiple patients for scRNAseq, CyTOF and FACS analysis, and the combination of 2 cohorts makes this a larger dataset than other, similar papers.

The study provides an in-depth exploration of monocytes and low-density neutrophils between mild and severe COVID-19. The authors interestingly identify immature neutrophils in severe COVID-19, providing an additional therapeutic target.

Standing in the field: The authors identify a monocyte subset in mild COVID-19 with an ISG signature; type I/III interferons have previously been found to be protective (Blanco-Melo et al, Cell, 2020 & Stanifer et al, BioRxiv, 2020). A different study has also shown a reduction in HLA-DR in severe COVID-19 who have respiratory failure (Giamarellos-Bourboulis et al, Cell Host & Microbe, 2020). The presence of LDN in Covid-19 patients was also described in another preprint (Morrissey et al, medRxiv).

Appropriate statistics: Sometimes. For the analyses with the Seurat package the statistics are appropriate. But for other figures it is unknown which test is used (Fig. 1D, 3A, 5, Suppl. Fig) or an inappropriate test is used (Fig. 2E). In general, it seems testing did not account for repeated sampling.

Viral model used: N/A

Translatability: The results are not close to bedside and are primarily descriptive.

Main limitations:

1. Patient cohort was not described, therefore it is unclear if the subset changes in severe COVID-19 are correlated with specific comorbidities or with patient treatment.

2. It is very difficult and sometimes not possible to find out which part of the data is used for which figure, or why some of the data points are not shown.

3. The different sample types for scRNAseq in cohort 2 (frozen PBMC, fresh PBMC, whole blood leukocytes) were combined in one analysis without integration or regression. This is not the generally accepted method to combine samples. For the samples of cohort 1 integration was used, but from Fig. 2B it seems the integration did not completely work as expected.

4. It is unclear whether samples were split for CyTOF/FACS and scRNAseq, or whether these were from different patients and/or time points. The links between cohort 1 and 2 are unclear.