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

Zintis Inde, Ben A. Croker, Clarence Yapp, Gaurav N. Joshi, Johan Spetz, Cameron Fraser, Xingping Qin, Le Xu, Brian Deskin, Elisa Ghelfi, Gabrielle Webb, Aaron F. Carlin, Yanfang Peipei Zhu, Sandra L. Leibel, Aaron F. Garretson, Alex E. Clark, Jason M. Duran, Victor Pretorius, Laura E. Crotty-Alexander, Chendi LiJamie Casey Lee, Chhinder Sodhi, David J. Hackam, Xin Sun, Aaron N. Hata, Lester Kobzik, Jeffrey Miller, Jin Ah Park, Douglas Brownfield, Hongpeng Jia, Kristopher A. Sarosiek

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbereabf8609
JournalScience Advances
Issue number34
StatePublished - Aug 2021

ASJC Scopus subject areas

  • General


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