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Authors: Kuai Yu et al.

Link to paper: https://www.researchsquare.com/article/rs-25869/v1

Journal/ Pre-Print: In Review Nature

Tags: Bioinformatics, Clinical, Immunology/Immunity

Research Highlights 

1. Characterisation of B and T lymphocyte subsets in PBMCs from COVID-19 patients at different stages of the disease using single-cell RNA-sequencing.

2. Patients with a severe disease state had an increased proportion of highly activated CD8+ T effectors with an exhausted and dysfunctional phenotype.

3. Identification of high expression of the prothymosin alpha (PTMA) in a specific CD8+ T memory subset. In vitro treatment with Ta1 (a peptide derived from PTMA) promoted the proliferation of activated T cells while reducing expression of certain activation markers, thereby preventing excessive activation.

Summary 

This study focuses on the characterisation of PBMC lymphocyte subsets from 10 COVID-19 patients at different disease stages using scRNA-seq. Plasma/activated B-cell expansion and low T-cell frequencies were characteristic of severe disease. Within the CD8+ T-cell compartment, severe disease patients had a high frequency of an activated, exhausted subset, and of a memory subset with stem cell-like features and high PTMA expression. Ta1 (a PTMA-derived peptide), promoted T-cell proliferation but limited expression of activation-associated genes in vitro. Ta1 administration to patients increased their lymphocyte counts. Ta1-driven proliferation may thus prevent excessive exhaustion and have a protective effect against severe COVID-19.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

Develop diagnostic tools for SARS-CoV2/COVID19: Authors discuss the idea of using the proportions of the identified subsets of lymphocytes as prognostic markers

Some suggestion that Ta1 administration could prevent severe disease

Study Type

· In silico study / bioinformatics study

· In vitro study

Strengths and limitations of the paper

Novelty: Characterised the presence of subsets of lymphocytes in COVID-19 patients at different stages of the disease; novel marker described that might perhaps also have some therapeutic potential.

Standing in the field: Several papers showed and investigated lymphopenia, however they did not have single-cell RNA sequencing data on patient at different disease stages.

Appropriate statistics: Yes, although results are derived from simple tests with relatively small sample sizes (n~3 per group)

Viral model used: SARS-CoV-2

Translatability: Low translatability. Observations need further investigation in a larger cohort and Ta1 administration requires formal clinical trialling

Main limitations: Small sample size per group.

Limited in stratifying patients according to clinical metadata.

Mild stage not studied, relevant for comparison.

Observations not easily interpreted in the context of other studies; some conclusions that look contradictory are not discussed further.

Given the expansion of the CD8+ stem-cell like T cell subset in severe disease, it is a little unclear whether this cell type and/or the high PTMA expression could really be protective.

Did not describe in details the different cell subsets. Would have been interesting to better compare SD with PS or even MD.

Where have the NK cells gone? These are not described and it is unclear if they were excluded from the analysis. If not, then there is some uncertainty regarding the exact nature of the cell types described.