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Authors: Carvelli et al

Link to paper: https://www.researchsquare.com/article/rs-27340/v1

Journal/ Pre-Print: Research Square

Tags; Immunology/Immunity, Cell Biology, Inflammation, Therapeutics, Drug discovery/ Drug repurposing

Research Highlights 

1. NK and T cells in ARDS COVID-19 patients have upregulated expression of immune checkpoint markers including PD-1, NKG2A and CD39

2. Anaphylatoxin C5a may play a role in initiation of the cytokine storm as it was increased in patients with severe COVID-19 pneumonia/ARDS and also in few paucisymptomatic patients

3. Presents potential clinical benefit in inhibiting T and NK cell exhaustion markers and/or blocking C5aR1 with mAb avdoralimab

Summary 

The authors studied 82 individuals (10 healthy controls, 10 paucisymptomatic, 34 pneumonia and 28 ARDS COVID-19 patients). They found that NK cells and T cells of the ARDS patients upregulated immune checkpoints including PD-1, NKG2A and CD39 compared to the other individuals in the study measured within 3 days of diagnosis. This increased immune checkpoint expression remained stable until day 10. Authors also found increased expression of C5a in the serum and its receptor C5aR1 on the myeloid cells in pneumonia and ARDS patients. They propose inhibition of C5aR1 and immune checkpoints as a potential treatment for severe COVID-19 patients.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

Understand the virology and/or cell biology of SARS-CoV2/COVID19

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19

Treat of SARS-CoV2/COVID19 positive individuals – repurposing C5aR1 inhibitors and immune checkpoint inhibitors as a potential treatment

Study Type

· In vitro study

· Patient Case study

Strengths and limitations of the paper

Novelty: It reports the exhaustion phenotype in NK cells and T cells. The same has been already reported by Zheng et al (Zheng et al, 2020, Cellular and molecular immunology),

however, not over the whole course of COVID-19, here the stability of the increased immune checkpoint expression is shown as well.

Standing in the field: In agreement. Both the exhaustion phenotype of NK cells and T cells and high expression of C5a in the serum have been reported in the literature.

Appropriate statistics: Using non-parametric testing in most of their experiments seems appropriate for small sample sizes. Completely missing statistics in Figure 4.

Viral model used: SARS-CoV2

Translatability: Suggests using immune checkpoint inhibitors and/or C5aR1 inhibitors (e.g. avdoralimab) as a potential treatment of COVID-19

Main limitations:

1) The data from the longitudinal follow up of pneumonia and ARDS patients are pooled so it is not shown whether there are any differences in these two groups regarding the immune checkpoints’ expression.

2) In the study of C5aR1 expression on myeloid cells, authors used the BALF of ARDS patients. In the supplementary figures, they have a superficial comparison to healthy controls. To draw conclusions about the C5aR1 increased expression in myeloid cells found in ARDS, it would be better to compare it to the other groups of individuals in their study.

3) They studied the effect on C5a on neutrophils and the potential of inhibition by avdoralimab (C5aR1 inhibitor), however, they measured the neutrophil activation only by CD11b expression. Looking at other markers of neutrophil activation would better support their claims.