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Review
. 2021 Feb 1:12:622738.
doi: 10.3389/fimmu.2021.622738. eCollection 2021.

Cytokine Storm as a Cellular Response to dsDNA Breaks: A New Proposal

Snehal Shabrish  1 , Indraneel Mittra  1
Affiliations
Review

Cytokine Storm as a Cellular Response to dsDNA Breaks: A New Proposal

Snehal Shabrish et al. Front Immunol. .

Abstract

Pathogenesis of cytokine storm is poorly understood. In this article we propose a new mechanism and suggest innovative therapeutic avenues for its prevention. We have reported that particles of cell-free chromatin (cfCh) that are released from the billions of cells that die in the body everyday can illegitimately integrate into genomes of healthy cells to trigger dsDNA breaks. The latter leads to apoptosis and/or intense activation of inflammatory cytokines in the affected cells. We hypothesise that a similar phenomenon of dsDNA breaks and inflammation is involved in cytokine storm. The abundant cfCh particles that are released from dying host cells following viral/microbial invasion initiate a cascading effect of more cell death resulting in a vicious cycle of further DNA damage, apoptosis and hyper-inflammation which culminate in cytokine storm. We propose that this unrelenting vicious cycle of cellular DNA damage and cytokine storm may be the underlying cause of high mortality from severe COVID-19. We discuss results of our preclinical studies wherein we have shown that endotoxin induced cytokine storm in mice can be reversed by three different agents that have the ability to inactivate cfCh. These agents may be worthy of investigation in clinical trials to reduce mortality from COVID-19.

Keywords: COVID-19; Cytokine storm; apoptosis; copper; dsDNA breaks; free radicals; inflammation; resveratrol.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Graphical Abstract
Graphical Abstract
Schematic illustration of a vicious cycle initiated by genomic incorporation of cfCh resulting in dsDNA breaks, apoptosis, and hyper-inflammation which culminate in cytokine storm.
Figure 1
Figure 1
Schematic illustration of activation of DDR and inflammation following illegitimate integration of cfCh into the genome.
Figure 2
Figure 2
DNA damage, apoptosis and inflammation in multiple organs and tissues induced by LPS can be prevented by concurrent treatment with cfCh inactivating agents. The above parameters were estimated at 72hrs following LPS treatment by indirect immuno-fluorescence. Mean (± SEM) values between groups were compared using non parametric one-way ANOVA (Kurskal—Wallis test) with Dunn’s multiple comparison method at the significance and confidence level of p = 0.05. MFI = Mean fluorescence intensity. Reproduced from ref (65).
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