Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 severity

• Type of Material: Article
• Authors: Zintis Inde, Harvard T.H. Chan School of Public Health; Clarence Yapp, Harvard Medical School; Gaurav N. Joshi, Emory University; Johan Spetz, Harvard T.H. Chan School of Public Health; Cameron Fraser, Harvard T.H. Chan School of Public Health; Brian Deskin, Harvard T.H. Chan School of Public Health; Elisa Ghelfi, Harvard T.H. Chan School of Public Health; Chhinder Sodhi, Johns Hopkins University; David J. Hackam, Johns Hopkins University; Lester Kobzik, Harvard T.H. Chan School of Public Health; Ben A. Croker, University of California San Diego; Douglas Brownfield, Harvard T.H. Chan School of Public Health; Hongpeng Jia, Johns Hopkins University; Kristopher A. Sarosiek, Harvard T.H. Chan School of Public Health
• Language: English
• Date: 2021-08-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abf8609
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 7
• Issue: 34
• Grant/Funding Information: This work was supported by funding from the HSPH Dean’s Fund for Scientific Advancement (K.A.S.), the HSPH National Institute for Environmental Health Sciences (NIEHS) Center (K.A.S., J.S.), R00CA188679 (K.A.S.), R01CA248565 (K.A.S.), R21AI149321 (H.J.), and R01AI148446 (H.J.), Harvard Center for Cancer Systems Pharmacology, U54CA225088 (C.Y.), Precancer Atlas Program, U2CCA233262 (C.Y.), National Cancer Institute, U2CCA233280 (C.Y.), and DARPA Biostasis, W911NF-19-2-0017 (C.Y.).
• Keywords: LUNG DEVELOPMENT; Science & Technology; APOPTOSIS; Multidisciplinary Sciences; MICE; REPLICATION; Science & Technology - Other Topics; ACE2; PROTEINS; SYNDROME-CORONAVIRUS; INFECTION; ACUTE RESPIRATORY SYNDROME; EXPRESSION

Abstract

Novel coronavirus disease 2019 (COVID-19) severity is highly variable, with pediatric patients typically experiencing less severe infection than adults and especially the elderly. The basis for this difference is unclear. We find that mRNA and protein expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, increases with advancing age in distal lung epithelial cells. However, in humans, ACE2 expression exhibits high levels of intra- and interindividual heterogeneity. Further, cells infected with SARS-CoV-2 experience endoplasmic reticulum stress, triggering an unfolded protein response and caspase-mediated apoptosis, a natural host defense system that halts virion production. Apoptosis of infected cells can be selectively induced by treatment with apoptosis-modulating BH3 mimetic drugs. Notably, epithelial cells within young lungs and airways are more primed to undergo apoptosis than those in adults, which may naturally hinder virion production and support milder COVID-19 severity.