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Authors: Campos Codo et al

Link to paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3606770&download=yes&redirectFrom=true

Journal/ Pre-Print: SSRN

Tags: Immunology/Immunity, Bioinformatics, Cell Biology, Proteomics, Therapeutics

Research Highlights

1. HIF1a mRNA and protein is enriched in monocytes from COVID19 patients.

2. Glucose enhances SARS-CoV-2 viral load and IL-1β/ACE2 transcription in monocytes. This is impaired by inhibiting glycolysis, HIF-1α and mitochondrial ROS.

3. Diminishing HIF-1α signaling in monocytes restores IFNγ production by co-cultured CD4+ T cell and the survival of A549 lung epithelial cells stimulated with conditioned media from SARS-CoV-2-infected monocytes.

Summary

Diabetics have poor COVID-19 prognosis while monocytes of COVID19 patients show elevated HIF-1α expression This study addresses the relationship between the two .Viral load was increased with glucose stimulation in peripheral monocytes from healthy donors, resulting in the transcription of IL-1β, which is hypothesised to contribute to lung pathology; the glycolysis inhibitor 2-DG blocked this. Pre-treating monocytes with an array of metabolic inhibitors showed that SARS-CoV-2-triggered mitochondrial ROS enhances HIF-1α, a strong inducer of IL-1β and glycolysis. This switch to aerobic glycolysis in SARS-CoV-2-infected monocytes, facilitated SARS-CoV-2 replication, inhibited T cell responses (proliferation and IFNγ production) and induced epithelial cell apoptosis. The authors highlight that COVID-19 patients might benefit from inhibition of mtROS/HIF-1α/glycolysis signaling.

Impact for SARS-CoV2/COVID19 research efforts

Understand the virology and/or cell biology of SARS-CoV2/COVID19: This study examines the effects of metabolism on SARS-CoV-2 replication in monocytes and the induction of cytokines.

Treat of SARS-CoV2/COVID19 positive individuals: The authors explore the reliance of SARS-CoV-2 on the glycolytic switch of cells and suggest that glycolysis could be targeted in the SARS-CoV-2 setting.

Study Type

· In silico study / bioinformatics study

· In vitro study

Strengths and limitations of the paper

Novelty: The novel insights from this study include the mtROS stimulating HIF-1α, resulting in a glycolytic switch in the SARS-CoV-2 setting. The authors use glycolysis, oxidated stress and HIF-1α inhibitors to illustrate the reliance of SARS-CoV-2 replication on this pathway.

Standing in the field: mTOR/HIF-1α pathway has been previously found to be altered in the SARS-CoV-2 infected setting (Appelberg et al, BioRxiv, 2020). The authors observed reduced proliferation of lymphocytes consistent with the CD4 and CD8 T cell reduction in COVID-19 patients (Mathew et al, BioRxiv, 2020). This study fits with existing literature suggesting a dysregulation in the HIF-1α pathway which may contribute to more permissive viral replication.

Appropriate statistics: Yes

Viral model used: HIAE-02 SARS-CoV-2/SP02/human/2020/BRA (Brazilian patient)

Translatability: Not close to bedside but translatable since these data suggest that the HIF-1α could be targeted for therapeutic gain. These data may also explain why diabetics with uncontrolled blood glucose are at higher risk of severe COVID19.

Main limitations:

1. Mechanistic studies performed using peripheral monocytes from healthy donors. Beyond the scope of this study, but would be interesting to compare monocytes from healthy donors, indivduals with controlled diabetes and those with uncontrolled disease (+/- COVID19)

2. Introduction is very brief, not explaining diabetes or glucose metabolism in much detail

3. If inhibiting the glycolysis pathway results in the dampening of type I/III interferons, but other papers have shown that type III interferons are required to control infection, how would the authors approach this issue if metabolic inhibitors are to be considered (Stanifer et al, BioRxiv, 2020)?

4. Would be good to show monocyte viability with different conditions and inhibtiors

5. Specific figure comments:

a. ACE2 and IL-1β without infection should be shown with different glucose concentrations (Figure 1)

b. In Figure 2C, ACE2 expression is higher with infection in monocytes; why is the same trend is not observed in intestinal epithelial organoids? (Lamers et al, Science, 2020)

c. No axis ticks for histograms so difficult to tell the scale of effect. Fig3E CoV2 and Bay85 look the same but that isn’t what the cumulative MFI says

d. Figure 4A CoV-2 does not seem lower in representative graph and CFSE dilution showed as several overlapping histograms rathe than a continuum

e. Fig 4C not clear if PI staining has worked, would be nice to have a positive control

f. Figure S3B TNF duplicated from 2-DG above