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

Wen Juan Tu, Michelle Melino, Jenny Dunn, Robert D. McCuaig, Helle Bielefeldt-Ohmann, Sofiya Tsimbalyuk, Jade K. Forwood, Taniya Ahuja, John Vandermeide, Xiao Tan, Minh Tran, Quan Nguyen, Liang Zhang, Andy Nam, Liuliu Pan, Yan Liang, Corey Smith, Katie Lineburg, Tam H. Nguyen, Julian D. J. Sng, Zhen Wei Marcus Tong, Keng Yih Chew, Kirsty R. Short, Roger Grand, Nabila Seddiki and Sudha Rao ()
Additional contact information
Wen Juan Tu: QIMR Berghofer Medical Research Institute
Michelle Melino: QIMR Berghofer Medical Research Institute
Jenny Dunn: QIMR Berghofer Medical Research Institute
Robert D. McCuaig: QIMR Berghofer Medical Research Institute
Helle Bielefeldt-Ohmann: The University of Queensland
Sofiya Tsimbalyuk: Charles Sturt University
Jade K. Forwood: Charles Sturt University
Taniya Ahuja: QIMR Berghofer Medical Research Institute
John Vandermeide: QIMR Berghofer Medical Research Institute
Xiao Tan: University of Queensland
Minh Tran: University of Queensland
Quan Nguyen: University of Queensland
Liang Zhang: NanoString Technologies Inc.
Andy Nam: NanoString Technologies Inc.
Liuliu Pan: NanoString Technologies Inc.
Yan Liang: NanoString Technologies Inc.
Corey Smith: QIMR Berghofer Medical Research Institute
Katie Lineburg: QIMR Berghofer Medical Research Institute
Tam H. Nguyen: QIMR Berghofer Medical Research Institute
Julian D. J. Sng: The University of Queensland
Zhen Wei Marcus Tong: The University of Queensland
Keng Yih Chew: The University of Queensland
Kirsty R. Short: The University of Queensland
Roger Grand: Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT)
Nabila Seddiki: Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT)
Sudha Rao: QIMR Berghofer Medical Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract In 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.

Date: 2023
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DOI: 10.1038/s41467-023-39341-4

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