In research just published in the authoritative scientific journal Nature Cell Biology, a mechanism of cellular DNA damage induced by the SARS-CoV-2 virus has been identified that causes cellular ageing and chronic inflammation.
This study explains pathological effects of the infection, even in the long term, and lays the foundation for new pharmacological treatments. In the publication, ICGEB researchers stand alongside top Italian research centres in studying the molecular basis of COVID-19.
An exaggerated inflammatory response to SARS-CoV-2 infection is behind the most harmful effects of COVID-19. It was known that some viruses were capable of inducing cellular DNA damage and that failure to repair the damage resulted in tumours, cellular senescence and chronic inflammation. This was the starting point for the team of scientists co-ordinated by Fabrizio d’Adda di Fagagna at IFOM in Milan, together with virologists from ICGEB, led by Alessandro Marcello, and Serena Zacchigna and Rossana Bussani from the University of Trieste for the analysis of the patients’ tissues.
“We have observed,” explains Alessandro Marcello, “that when the virus replicates in infected cells, it rapidly depletes the precursor resources needed for nucleic acid synthesis. This causes damage to cellular DNA that must be repaired. At the same time, certain proteins of the virus, called Orf6, Nsp13 and N, interfere with cellular repair mechanisms, causing cellular senescence and production of inflammatory cytokines. The so-called ‘cytokine storm’ underlies the pulmonary pathology characteristic of COVID-19, but also the neurological symptoms we find in ‘long COVID’, which can persist even long after infection.”
“Importantly,” confirms Serena Zacchigna, “the effects found in the cellular models studied in the laboratory were confirmed in the tissues of patients with COVID-19, thus in the natural context of the infection.”
The implications of the study are not limited to understanding the molecular mechanisms of the infection, but lay the foundations for a drug therapy capable of alleviating the complications of the infection, especially the long-term ones.
“Three years ago in Italy, we were the first in Europe to tackle a virus that was unknown at the time,” Alessandro Marcello concludes, “in a very short time, scientific research has led to fundamental results in containing the epidemic, such as vaccines and antiviral drugs. It is extremely important to maintain a high level of attention and support excellent research so as not to be unprepared for future emergencies.”
Collaborators in the study include: IFOM, ICGEB, based in Area Science Park, IGM-CNR in Pavia, San Raffaele in Milan (Matteo Iannacone), the University of Padua (Chiara Rampazzo), the Besta Neurological Institute (Paola Cavalcante), the University of Trieste (Serena Zacchigna and Rossana Bussani) and the University of Palermo (Claudio Tripodo).
Link to paper
Gioia, U., Tavella, S., Martínez-Orellana, P. et al. SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence. Nat Cell Biol (2023). https://doi.org/10.1038/s41556-023-01096-x