SARS-CoV-2, the causative agent of COVID-19, has been the focus of intense research since its detection in late 2019. It is known that viral infection affects several cellular processes, including senescence and inflammation, and prior studies also point toward SARS-CoV-2 infection causing engagement of components of the DNA damage repair machinery. However, questions remain about the virus’s effect on genome integrity and the underlying mechanisms. 

Gioia et al utilized a range of methodologies to address these unknowns, including protein immunoblotting, quantitative immunofluorescence microscopy, comet assays, and quantitative real-time PCR. Results of their in vitro studies indicated that SARS-CoV-2 infection causes the accumulation of cellular DNA damage through the inhibition of DNA replication and repair by the viral ORF6, NSP13, and N proteins. The authors also observed that virus-induced DNA damage resulted in expression of a selection of pro-inflammatory cytokines. 

The authors checked for similar effects in vivo by analyzing formalin-fixed paraffin-embedded tissue from SARS-CoV-2-infected mice and humans. Slides were scanned and combined in situ RNA hybridization/ immunohistochemistry images were analyzed using the HALO® ISH-IHC module to quantify cells positive for viral RNA and host biomarkers. The Highplex FL module was utilized to quantify cells positive for multiple host cell biomarkers in immunofluorescence images. Results from infected mouse and human tissues were consistent with the authors’ in vitro results, exhibiting DNA damage and disruption of pathways required for DNA replication and repair, and also indicated development of cellular senescence. 

Gioia et al conclude that the robust inflammation observed in COVID-19 patients is a product of the host immune response and a cell-intrinsic inflammatory response elicited by DNA damage caused by SARS-CoV-2 infection. Lastly, the authors propose that their findings could inform future studies into SARS-CoV-2-induced cellular senescence and the mechanisms underlying long COVID.