In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting

Author:

Tu Wen Juan,Melino Michelle,Dunn Jenny,McCuaig Robert D.,Bielefeldt-Ohmann HelleORCID,Tsimbalyuk Sofiya,Forwood Jade K.ORCID,Ahuja Taniya,Vandermeide JohnORCID,Tan Xiao,Tran Minh,Nguyen Quan,Zhang Liang,Nam Andy,Pan Liuliu,Liang YanORCID,Smith Corey,Lineburg KatieORCID,Nguyen Tam H.,Sng Julian D. J.ORCID,Tong Zhen Wei Marcus,Chew Keng Yih,Short Kirsty R.ORCID,Le Grand RogerORCID,Seddiki NabilaORCID,Rao SudhaORCID

Abstract

AbstractIn vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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