Several host factors, including the virus-induced oxidative stress and redox-sensitive pathways, are involved in the regulation of specific steps of respiratory virus replication and inflammatory response. The recent SARS-CoV-2 pandemic has also highlighted the importance of Angiotensin Converting Enzyme 2 (ACE2) expression in favoring viral entry, but also in regulating the cell response to infection, thanks to its ability to modulate antioxidant and anti-inflammatory responses. ACE2/Spike interaction is strictly dependent on cysteine residues present on both the proteins, keeping them in oxidized form that increases the affinity for ACE2 receptor and favors the viral entry.
Furthermore, the addition of a derivative of glutathione, the main intracellular antioxidant, on influenza virus (IV)-infected cells, by restoring reducing condition and interfering with the protein disulfide isomerase, impaired Hemagglutinin (HA) folding and viral replication.
On the basis of these evidence, treatment with redox-modulating compounds represents a promising approach to impair both viral entry or by regulating the expression of ACE2 and its related antioxidant pathways.
In the present proposal we will evaluate:
a) the effect of thiols on disulfide bounds of Spike and HA, by adding the molecules at different steps of infection;
b) the expression of ACE2 and its related antioxidant pathways in cells already infected with CoV or IV and treated with thiols;
c) the potential anti-inflammatory activity of thiol compounds mediated by redox-sensitive ACE2 pathways.
Our results will provide new knowledge on the mechanisms underlying SARS-CoV-2 and IV pathogenesis and suggest new therapeutic approaches based on redox-modulating compounds impairing oxidative stress and regulating ACE2 expression. This approach would have a beneficial effect at the early stage of viral infection or by impairing viral replication and virus-induced lung injury when infection has already been occurred.
The use of redox-modulating compounds is a promising therapeutic approach by the rescue of reducing conditions in the cell and regulating the inflammatory response as well as in impairing the Spike/ACE2 binding and consequently the viral entry.
The obtained results will contribute to clarify the mechanisms at the basis of lung pathogenesis caused by respiratory viruses, such as SARS-CoV-2 and influenza virus as well as the regulation of ACE2 expression and its redox-related pathways.
The use of redox-modulating compounds represents a promising approach to treat different types of viral infections. Indeed, the possibility to modulate redox state, in terms of reducing oxidative stress or regulating ACE expression and redox-related pathways important for viral replication or antioxidant response, would have a beneficial effect during the early stage of viral infection (Spike/ACE2 binding or HA/Sialic Acid) or by impairing viral replication and virus-induced lung injury when infection has been already occurred.