Researchers from IFOM in Milan and CNR-IGM in Pavia have identified the molecular bases of the aggressiveness and deleterious effects of SARS-CoV-2: the virus causes damage to the cell's DNA and prevents it from repairing it, thus causing cellular senescence and chronic inflammation. The study, published in the authoritative scientific journal Nature Cell Biology, lays the conceptual foundations for developing new treatments to limit the effects of SARS-CoV-2 infection.
Although several progresses have been made in terms of diagnosis, treatment and prevention since the first cases in December 2019, it is still not clear why SARS-CoV-2 has such a dramatic impact on human health compared to other respiratory viruses. The IFOM group led by Fabrizio d'Adda di Fagagna, specialized for 20 years in the study of the DNA damage response, a fundamental process through which the cells of our body protect us from the deleterious effects of various physiological and pathological events, including cancer and viral infections, discovered one reasons that make this virus particularly aggressive and the results are published today in the authoritative scientific journal Nature Cell Biology.
“All viruses are parasites, you know. – explains Fabrizio d’Adda di Fagagna, head of the IFOM laboratory “Risposta al danno al DNA e Senescenza Cellulare” and Research Director at IGM-CNR of which he coordinates the IGM Research Unit at IFOM – They enter a cell and begin to exploit everything made available by the infected cell in order to replicate and spread. SARS-CoV-2 is a particularly greedy and skilled virus. In our laboratory we wondered how this "hacking" operation by the virus takes place and whether there is a connection with those processes that we study every day in pathological areas that only apparently look distant, such as tumors, genetic diseases and age-related disorders: all events, in fact, tightly associated with DNA damage accumulation”
From the left: Ubaldo gioia, Sara Tavella and Fabrizio d’Adda di Fagagna
Blue: Nuclear DNA, Red: DNA damage marker, Green: SARS-CoV-2 protein
Given these postulates, the first authors of this study Ubaldo Gioia and Sara Tavella, through the use of different in vitro cellular systems, have identified the molecular causes underlying the deleterious effects of COVID-19, and have found confirmation in vivo, both in mouse model systems of infection and in post-mortem tissues from COVID-19 patients.
What we have observed - Gioia and Tavella illustrate - is that SARS-CoV-2, once in the cell, hijacks its fundamental processes, forcing it to stop producing deoxynucleotides, the building blocks of DNA, to make it produce ribonucleotides, i.e. the "bricks" necessary to synthesize the RNA of the cell and that of the virus above all. It is precisely this alteration of the cellular processes carried out by the virus to its advantage that allows the explosive viral replication within cells infected by SARS-CoV-2. A dramatic consequence of this exploitation of the cellular machinery by the virus is the lack of deoxynucleotides: “the cell – the researchers describe – cannot adequately replicate its DNA and accumulates damage in its genome. Furthermore - continue Gioia and Tavella - we discovered that the virus, in addition to causing DNA breakage due to lack of deoxynucleotides, also interferes with the cellular repair mechanisms of such damaged DNA, inhibiting 53BP1, a protein essential for the repair process".
These two events, DNA damage generation and inhibition of its repair, have dramatic effects on the cell infected with SARS-CoV-2 and on patients "Among them - explains d'Adda di Fagagna - certainly the premature aging of cells, a process known as cellular senescence, and the associated production of inflammatory cytokines. It is no coincidence that the main cause of the most severe symptoms in patients with COVID-19 is precisely an excessive production of inflammatory cytokines, also known as 'cytokine storm'. Based on the results obtained, we have highlighted how the accumulation of damage to DNA, the only irreplaceable component of our cells, can make an important contribution to the inflammatory storm unleashed by the virus". But the researchers didn't stop there. "By providing the infected cells with deoxynucleotide supplements - explain Gioia and Tavella - we have shown that, by reducing the DNA damage caused by the virus, we also reduce the levels of inflammation".
“It is important to underline - concludes d'Adda di Fagagna - that cellular senescence and chronic inflammation are the basis of the aging process and in fact many scientists are more and more frequently gathering evidence of accelerated aging in patients with severe COVID-19. In this sense, it will also be important to study the correlation between our new discoveries and conditions such as the so-called long COVID, to develop new pharmacological treatments that limit the effects of this pathology."
This study would not have been possible without the collaboration of the ICGEB laboratories of Trieste (Alessandro Marcello and Serena Zacchigna) and of the San Raffaele Hospital of Milan (Matteo Iannacone), of the University of Padua (Chiara Rampazzo), of the Besta Neurological Institute (Paola Cavalcante) and the University of Palermo (Claudio Tripodo).