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

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.