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Author Notes:

sarosiek@hsph.harvard.edu

K.S. and Z.I. conceived the study. Z.I., C.Y., B.A.C., B.D., E.G., D.B., and K.S. analyzed data. Z.I., B.D., H.J., and G.N.J conducted imaging experiments. Z.I., J.S., and C.F. conducted BH3 profiling experiments. C.S., D.J.H., and H.J. provided samples for analysis. L.K. conducted pathological analysis of samples. Z.I. and K.S. wrote the manuscript. All authors edited and approved the final manuscript.

We thank the members of our labs for their comments and suggestions on this work, especially Kaitlyn Webster for assistance with image quantification. We thank Olesja Popow (Dana Farber Cancer Institute) for providing training data for the UNet model and Zoltan Maliga (Harvard Program in Therapeutic Science) for imaging the human TMA samples and advising on staining protocols. Imaging experiments were supported in part by the Emory University Integrated Cellular Imaging Microscopy Core.

The authors declare no competing interests.

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Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • ACUTE RESPIRATORY SYNDROME
  • SYNDROME-CORONAVIRUS
  • LUNG DEVELOPMENT
  • APOPTOSIS
  • INFECTION
  • ACE2
  • MICE
  • REPLICATION
  • EXPRESSION
  • PROTEINS

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

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Journal Title:

SCIENCE ADVANCES

Volume:

Volume 7, Number 34

Publisher:

Type of Work:

Article | Preprint: Prior to Peer Review

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.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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