Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 severity.
Zintis IndeBen A CrokerClarence YappGaurav N JoshiJohan K E SpetzCameron FraserXingping QinLe XuBrian DeskinElisa GhelfiGabrielle WebbAaron F CarlinYanfang Peipei ZhuSandra L LeibelAaron F GarretsonAlex E ClarkJason M DuranVictor G PretoriusLaura E Crotty AlexanderChendi LiJamie Casey LeeChhinder SodhiDavid J HackamXin SunAaron N HataLester KobzikJeffrey W MillerJin-Ah ParkDouglas G BrownfieldHongpeng JiaKristopher A SarosiekPublished in: Science advances (2021)
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.
Keyphrases
- sars cov
- endoplasmic reticulum stress
- induced apoptosis
- respiratory syndrome coronavirus
- coronavirus disease
- cell cycle arrest
- cell death
- angiotensin converting enzyme
- angiotensin ii
- single cell
- oxidative stress
- pi k akt
- signaling pathway
- binding protein
- middle aged
- poor prognosis
- early onset
- mesenchymal stem cells
- bone marrow
- gene expression
- stem cells
- small molecule
- protein protein
- replacement therapy
- bioinformatics analysis