The vaccination campaigns launched during the COVID-19 pandemic enabled the development of a relative immunity against the SARS-CoV-2 virus. However, immunity does fall off over time and may fare less well against newly-arriving variants. It thus remains vital to continue developing new therapies, with the goals of extending the current armamentarium and protecting the most vulnerable populations.
For a study published in 2021 in Cell Discovery, IDMIT researchers teamed with Australian colleagues at the QIMR Berghofer Medical Research Institute to report the discovery of a nuclear localization signal within ACE2 (the surface membrane protein to which the virus spike protein attaches) that, in the setting of SARS-CoV-2 infection and with the aid of an adaptor protein, translocates ACE2 to the cell's nucleus (taking on the name NACE2) to enable mechanisms essential for viral replication.
Following up on that earlier work, the research partners have published a new study in Nature Communications to show how a specific peptide inhibitor (NACE2i) developed by the Australian team members targets the NACE21 pathway and affects viral replication in vivo.
In a hamster model of SARS-CoV-2 infection, they showed that administration of NACE2i 1) inhibits viral replication, 2) prevents macrophage-induced lung inflammation, and 3) increases infiltration of natural killer (NK) cells in the bronchioli.
In lung tissues, the researchers used spatial transcriptomic analysis (combining high throughput profiling of gene expression, cells and signaling cascades) to establish the specific transcriptional signature associated with SARS-CoV-2 infection and the treatment of inflammation with NACE2i. That peptide induced an increase in the recruitment of the methylated form of ACE2 in the bronchiolar epithelium cells of the infected hamsters. The researchers also observed an increase in methylated histone H3 (H3K27ac). NACE2i thus appears to epigenetically reprogram NACE2, and in so doing, disarms SARS-CoV-2 and keeps it from replicating itself in the cell. Thereafter, the reprogrammed ACE2 returns to the cell surface, where it acts as a lock to prevent SARS-CoV-2 entry in the cell.
The two involved epigenetic modifications were also found in the monocytes of recovering COVID-19 patients and in vaccinated individuals, in parallel with a decrease in SARS-CoV-2 spike protein expression. Together, these observed modifications suggest the deployment of an epigenetic imprint associated with a reduced latent viral reservoir in monocytes/macrophages, and increased immunity against SARS-CoV-2.
The nuclear form of ACE2 is a therapeutic target of interest in COVID-19 and particularly in the "long" versions of it, for which there are no current treatments. The promising preclinical results obtained for it position NACE2i as an adjuvant therapy of interest to strengthen the efficacy of current SARS-CoV-2 vaccines, offering more long-term protection against the virus and its variants.