A feedback loop between DNA damage, genomic instability, and cytoplasmic DNA sensing contributes to cytokine production in COVID-19

Abstract

Since the onset of the COVID-19 pandemic, several studies have investigated the inflammatory responses triggered by SARS-CoV-2 infection. In 2021, it was proposed that the cytokine storm observed in patients with severe COVID-19 may be initiated by sensing of cytoplasmic DNA released by micronuclei, which arises as a consequence of virus-induced genomic instability. Subsequent studies have described the presence of micronuclei and other genotoxic and cytotoxic markers in COVID-19 patients. However, the association between the development of a cytokine storm and cytoplasmic DNA sensing remains to be fully elucidated. In this review, we summarize current evidence on the dysregulated cytokine production in response to the detection of genetic material during SARS-CoV-2 infection. We focused mainly on the dysregulated production of cytokines induced by the activation of cytosolic DNA sensing pathways that promote inflammation. We emphasize the need to analyze the contribution of these signaling complexes to COVID-19 pathophysiology. DNA sensing amplifies the inflammatory response and plays a crucial role in the pathogenesis of severe disease manifestations observed in infected patients. Understanding this complex interplay can provide insights into potential therapeutic targets aimed at mitigating the hyper-inflammatory responses seen in severe COVID-19 cases.

Keywords: AIM2; COVID-19; Cytokine storm; Micronucleus; NLRP3; cGAS-STING.

Fig. 1

Potential pro-inflammatory response triggered by the persistent detection of cytoplasmic DNA in severe COVID-19. After internalization of viral material, immune cells can produce reactive oxygen species (ROS), potentially damaging host DNA and activating the ATR/ATM pathways. This leads to genomic instability, cell cycle dysregulation, DNA repair, and/or apoptosis. cfChPs can produce ROS by mtDNA damage. A feedback loop between mtDNA damage induced by ROS and ROS overproduction by mitochondrial dysfunction activates the NLRP3 and AIM2 inflammasomes, promoting IL-1β and IL-18 maturation and cell death with pro-inflammatory effects (pyroptosis) by activation of gasdermin D (GSDMD). NLRP3 activation can also be triggered by SARS-CoV-2 viroporins, P2X7/ATP, mtDNA, or self-DNA signaling through AIM2. Additionally, cGAS-STING activity can be induced by cfCh, mtDNA and nuclear DNA from MN released to the cytoplasm. The endosomal receptor TLR-9 can detect self-mtDNA and cfDNA from neighboring apoptotic cells. All of these signaling events lead to IRF and NF-κB pathway activation and overproduction of several cytokines and chemokines, promoting overwhelming inflammation