Researchers from the IFOM of Milan and the Institute of Molecular Genetics of the National Research Council of Pavia (CNR-IGM), with the contribution of the virologists of the ICGEB of Trieste, have identified the molecular basis of the aggressiveness and deleterious effects of SARS-CoV-2: the virus would cause damage to the cell’s DNA and would prevent it from repairing them, thus causing cellular senescence and chronic inflammation.
The study lays the foundations for developing new pharmacological treatments that limit the effects of SARS-CoV-2. Although several advances have been made in terms of diagnosis, treatment and prevention since December 2019, it is still not clear why SARS-CoV-2 has such a serious 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 response to DNA damage, a fundamental process through which the cells of our body protect us from the deleterious effects of various physiological and pathological processes, including tumors and viral infections, discovered one of the reasons that make this virus particularly aggressive and the results were published in the authoritative scientific journal Nature Cell Biology.
“All viruses, as we know, are parasites – explains Fabrizio d’Adda of Fagagna, head of the IFOM laboratory “Response to DNA damage and Cellular Senescence” and Research Director at the CNR-IGM of Pavia – They enter a cell and start to exploit everything made available by the infected cell to replicate and spread. E SARS-CoV-2 is a particularly greedy and clever virus. In our laboratory we asked ourselves how this ‘hacking’ operation by the virus takes place and whether there could be a connection with those processes that we study every day in pathological areas that are only apparently distant, such as tumors, genetic diseases and conditions related to aging: all events united by the accumulation of DNA damage”.
Starting from these premises, the first authors of this study, the IFOM researchers Ubaldo Gioia and Sara Tavella, have identified, through the use of different in vitro cellular systems, 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 derived from patients affected by COVID-19. What we have observed, Gioia and Tavella illustrate, is that SARS-CoV-2, once it enters 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” that are used to synthesize the RNA of the cell and, above all, that of the virus.
It is precisely this alteration of the cellular process operated by the virus to its own advantage that allows the explosive viral replication within the cell infected by SARS-CoV-2.” A dramatic consequence of this exploitation of cellular mechanisms by the virus appears to be the deoxynucleotide deficiency: “the cell – the researchers describe – cannot adequately replicate its DNA and accumulates damage in its genome. Furthermore – continue Gioia and Tavella – we have discovered that the virus, in addition to cause DNA breakage due to lack of deoxynucleotides, it also interferes with cellular repair mechanisms of this damaged DNA, inhibiting the 53BP1 protein essential for the repair process”. These two events, DNA damage and inhibition of its repair, have dramatic effects on the SARS-CoV-2 infected cell and on patients.
“Among these – comments d’Adda di Fagagna – certainly the premature aging of cells, called cellular senescence, and the associated production of inflammatory cytokines. It is no coincidence that the main cause of the most serious symptoms in patients suffering from COVID-19 is precisely an excessive production of inflammatory cytokines, also known as a ‘cytokine storm’ Based on the results obtained we have shown that the accumulation of DNA damage, the only irreplaceable component of our cells, can make an important contribution to the inflammatory storm triggered by the virus”. But the researchers didn’t stop there. “By providing the infected cells with a deoxynucleotide supplement – 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 – specifies d’Adda di Fagagna – that cellular senescence and chronic inflammation are at the basis of aging processes, whether physiological or pathological, and in fact many scientists are increasingly discovering evidence of accelerated aging in cases of severe cases of 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 – concludes the researcher – would not have been possible without the indispensable collaboration of the ICGEB laboratories in Trieste conducted by colleagues Alessandro Marcello and Serena Zacchigna who carried out the experiments of viral infection and analysis of material from patients”. In addition to the ICGEB, San Raffaele of Milan (Matteo Iannacone), the University of Padua (Chiara Rampazzo), the Besta Neurological Institute (Paola Cavalcante) and the University of Palermo ( Claudius Tripodo).