Authors: Shiyu Li et al.

Link to paper: https://www.researchsquare.com/article/rs-31620/v1

Journal/ Pre-Print: Research square

Tags: Immunology/Immunity, T cell responses, Bioinformatics, Therapeutics

Research Highlights 

1. In vitro stimulation of PBMCs of recovered COVID-19 patients with S protein + vMIP-II treatment increased the ratio central memory CD8 T cells (TCM): effector memory CD8 T cells (TEM) within the total memory CD8 T cell pool.

2. Gene expression profiling of untreated versus vMIP-II treated CD8 T cells by RNASeq indicated vMIP-II changes the expression of genes encoding for chemokine receptors and protein phosphorylation pathways. This was validated by qRT-PCR and few in vitro experiments, which include evidence of lower expression of a G protein α subunit, and decreased phosphorylation of MAPK/ERK and Akt.

3. vMIP-II treatment seems to increase the mitochondrial potential of CD8 T cells compared to non-treated cells.

Summary 

The paper describes the potential benefit of treating COVID-19 patients with the chemokine inhibitor vMIP-II by ameliorating their reported lymphopenia/lymphocyte overreaction. A limited clinical trial showed that vMIP-II treatment helps recovery of lung lesions. Further experiments were mostly done by in vitro stimulation of PBMCs with recombinant SARS-COV2 S protein in the presence or not of vMIP-II treatment. The authors claim that vMIP-II treatment favours the differentiation of effector memory CD8 T cells into a central memory phenotype, but don’t investigate how de-differentiation might occur. In addition, the decreased frequencies of exhausted cells (PD1+TIM3+) found after vMIP-II treatment might suggest weak activation rather than apoptosis or higher proliferation ability. Transcriptional profiling of vMIP-II treated cells showed downregulation of genes linked to chemokine signalling and phosphorylation pathways, which was at least partially validated by qRT-PCR and in vitro assays. Overall this paper critically lacks evidence to conclude whether vMIP-II has therapeutic potential and its mechanism of action.

Impact for SARS-CoV2/COVID19 research efforts

Possible new therapy for SARS-CoV2/COVID-19 patients

Study Type

· In silico study / bioinformatics study

· In vitro study

· Clinical Cohort study – not a cohort but very limited number of patients

Strengths and limitations of the paper

Novelty: Potential use of a broad-spectrum chemokine receptor inhibitor (vMIP-II) to treat COVID-19 patients.

Standing in the field: Limited previous data on this topic

Appropriate statistics: Not detailed sufficiently. Sample size too small and no account is taken of multiple groups. No technical replicates. 

Viral model used: recombinant SARS-Cov2 S protein (S1 and S2 subunits) and COVID-19 patients from Wuhan.

Translatability: To test the efficacy of this drug (chemokine receptor inhibitor) it would require a better study design with control group and much larger cohort.

Main limitations:

- Just non-severe cases (10) and asymptomatic people (5) participated in the clinical trial. From the symptomatic patients, 5 received vMIP-II. No data is presented concerning their viral load.

- The treatment seems to enhance lung recovery in 5 patients, however as mild COVID-19 patients can have spontaneous recovery, it would be important to also present the CT images from the symptomatic untreated group, which was not done.

- Methods choice and study design were not well described for every experiment. Abbreviations are not explained, and how T cell subsets or cytokine production were assessed is not clear.

- Results are mostly limited to in vitro stimulated T cells (with recombinant S protein with/without vMIP-II).

- One of the major claims of the paper is that vMIP-II treatment benefits formation of central memory CD8 T cells, however just representative flow cytometry plots are shown, and no quantification can be found (for both frequencies and numbers of T cell subsets).

- They only looked at CD8 T cell memory phenotype after in vitro stimulation rather than directly from COVID-19 patient samples.

- Overall, the paper makes strong statements and claims causation effects without even strong supportive evidences of correlation between different results.