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.
Original language | English |
---|---|
Article number | 3680 |
Pages (from-to) | 1-21 |
Number of pages | 21 |
Journal | Nature Communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jun 2023 |
Externally published | Yes |
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In: Nature Communications, Vol. 14, No. 1, 3680, 06.2023, p. 1-21.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting
AU - Tu, Wen Juan
AU - Melino, Michelle
AU - Dunn, Jenny
AU - McCuaig, Robert D.
AU - Bielefeldt-Ohmann, Helle
AU - Tsimbalyuk, Sofiya
AU - Forwood, Jade K.
AU - Ahuja, Taniya
AU - Vandermeide, John
AU - Tan, Xiao
AU - Tran, Minh
AU - Nguyen, Quan
AU - Zhang, Liang
AU - Nam, Andy
AU - Pan, Liuliu
AU - Liang, Yan
AU - Smith, Corey
AU - Lineburg, Katie
AU - Nguyen, Tam H.
AU - Sng, Julian D.J.
AU - Tong, Zhen Wei Marcus
AU - Chew, Keng Yih
AU - Short, Kirsty R.
AU - Le Grand, Roger
AU - Seddiki, Nabila
AU - Rao, Sudha
N1 - Funding Information: We are grateful to all participants in this study. We thank the “Oncodesign team” for the hamster in vivo experiments. We would like to thank the QIMR Berghofer Scientific Services for their invaluable assistance in this work, particularly the core histology service for their extensive optimization of antibodies in this study for hamster tissue and the core microscopy facility for assistance with data analysis. We thank Nigel Waterhouse (Microscope Facility, QIMRb) for his assistance with the ANDOR WD Revolution super-resolution microscopy and microscopy data analysis. We thank Melissa Caspar (Metagene/ASI) for her assistance with the ASI Digital Pathology system. We thank Jyothy Raju, Pauline Crooks, Laetitia LeTexier, and Archana Panikkar for PBMC preparation. We also thank Amanda Bain for assisting with the logistics of the animal and human studies. J.M., and T.A. are supported by QIMRb PhD scholarships. C.S. and K.L. are supported by the Medical Research Future Fund (MRFF grant APP2005654). Q.N., M.T. and X.T. are supported by the Australian Research Council (ARC DECRA grant DE190100116), National Health & Medical Research Council (NHMRC Project Grant 2001514 and NHMRC Investigator Grant GNT2008928 to Q.N) and the University of Queensland Scholarship. K.R.S is supported by NHMRC investigator grant 2007919. We thank Clive Berghofer and Lyn Brazil (and others) for their generous philanthropic donations providing research support for this study to the Rao lab at QIMR Berghofer MRI. We also like to thank Queensland Health for funding the QIMRb COVID-19 Research Program. We are grateful for the support of IDMIT infrastructure by the French government: Investments for the Future program for infrastructures (PIA) through the ANR-11-INBS-0008 grant. Funding Information: We are grateful to all participants in this study. We thank the “Oncodesign team” for the hamster in vivo experiments. We would like to thank the QIMR Berghofer Scientific Services for their invaluable assistance in this work, particularly the core histology service for their extensive optimization of antibodies in this study for hamster tissue and the core microscopy facility for assistance with data analysis. We thank Nigel Waterhouse (Microscope Facility, QIMRb) for his assistance with the ANDOR WD Revolution super-resolution microscopy and microscopy data analysis. We thank Melissa Caspar (Metagene/ASI) for her assistance with the ASI Digital Pathology system. We thank Jyothy Raju, Pauline Crooks, Laetitia LeTexier, and Archana Panikkar for PBMC preparation. We also thank Amanda Bain for assisting with the logistics of the animal and human studies. J.M., and T.A. are supported by QIMRb PhD scholarships. C.S. and K.L. are supported by the Medical Research Future Fund (MRFF grant APP2005654). Q.N., M.T. and X.T. are supported by the Australian Research Council (ARC DECRA grant DE190100116), National Health & Medical Research Council (NHMRC Project Grant 2001514 and NHMRC Investigator Grant GNT2008928 to Q.N) and the University of Queensland Scholarship. K.R.S is supported by NHMRC investigator grant 2007919. We thank Clive Berghofer and Lyn Brazil (and others) for their generous philanthropic donations providing research support for this study to the Rao lab at QIMR Berghofer MRI. We also like to thank Queensland Health for funding the QIMRb COVID-19 Research Program. We are grateful for the support of IDMIT infrastructure by the French government: Investments for the Future program for infrastructures (PIA) through the ANR-11-INBS-0008 grant. Publisher Copyright: © 2023, Crown.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85163725514&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39341-4
DO - 10.1038/s41467-023-39341-4
M3 - Article
C2 - 37369668
AN - SCOPUS:85163725514
SN - 2041-1723
VL - 14
SP - 1
EP - 21
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3680
ER -