Impact of SARS-CoV-2 variants on genome integrity and their involvement in inflammation and neuropathogenesis

Severe COVID-19 is characterized by the inefficient suppression of early stages of infection followed by an exacerbated response once the virus has proliferated, resulting in hyperinflammation and cytokine storm, acute respiratory syndrome, tissue damage, multi-organ failure, with long-term effects known as Long COVID.

SARS-CoV-2 infection has been reported to compromises genome integrity by causing virus-induced DNA damage (VIDD) through the viral proteins Orf6 and NSP13, and by inhibiting DNA repair through the Nucleocapsid (N) protein. This leads to activation of proinflammatory pathways and virus-induced senescence (VIS) with autocrine/paracrine activity. Recent variants of concern have shown recurrent substitutions in Orf6, N and NSP13, and enhanced expression of Orf6 and N including the production of a novel sub-genomic RNA encoding a truncated form of N.

OBJECTIVES

This project aims to:

• get a better insight into the molecular mechanisms behind VIDD and VIS in the context of neuroinflammation.
• characterize the effect of the aminoacidic changes accumulated with evolution.
• better understand the endocrine and paracrine consequences of SARS-CoV-2-mediated DNA damage, in the contest of the neuronal cells.
• pave the way for a senolytic treatment.
• target VIS and virus replication to alleviate long-term consequences of infection in a model of neuropathogenesis.