Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53.

Autor:	Lee JD; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jdlee@post.harvard.edu., Menasche BL; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Mavrikaki M; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Uyemura MM; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Hong SM; Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Kozlova N; Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Wei J; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Alfajaro MM; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Filler RB; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Müller A; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Saxena T; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Posey RR; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Cheung P; Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA., Muranen T; Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Heng YJ; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Paulo JA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Wilen CB; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Slack FJ; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: fslack@bidmc.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Dec 26; Vol. 42 (12), pp. 113478. Date of Electronic Publication: 2023 Nov 21.
DOI:	10.1016/j.celrep.2023.113478
Abstrakt:	Coronavirus disease 2019 (COVID-19) remains a significant public health threat due to the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and Middle East respiratory syndrome (MERS)-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here, we use our recently developed integrative DNA And Protein Tagging methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants. Competing Interests: Declaration of interests J.D.L. is listed as a co-inventor on a patent describing the iDAPT technology. Yale University (C.B.W. and J.W.) has a patent on host-directed therapeutics for COVID-19. C.B.W. is a consultant for Exscientia. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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