Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53
Jonathan D. Lee,
Bridget L. Menasche,
Maria Mavrikaki,
Madison M. Uyemura,
Su Min Hong,
Nina Kozlova,
Jin Wei,
Mia M. Alfajaro,
Renata B. Filler,
Arne Müller,
Tanvi Saxena,
Ryan R. Posey,
Priscilla Cheung,
Taru Muranen,
Yujing J. Heng,
Joao A. Paulo,
Craig B. Wilen,
Frank J. Slack
Affiliations
Jonathan D. Lee
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Bridget L. Menasche
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
Maria Mavrikaki
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Madison M. Uyemura
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Su Min Hong
Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Nina Kozlova
Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Jin Wei
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
Mia M. Alfajaro
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
Renata B. Filler
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
Arne Müller
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Tanvi Saxena
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Ryan R. Posey
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
Priscilla Cheung
Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Taru Muranen
Department of Genetics, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Yujing J. Heng
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Joao A. Paulo
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Craig B. Wilen
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
Frank J. Slack
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; Corresponding author
Summary: 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.
