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

Abstract

Angiotensin-converting enzyme 2 (ACE2) maintains cardiovascular and renal homeostasis but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal agent of novel coronavirus disease 2019 (COVID-19). COVID-19 disease severity is typically lower in pediatric patients than adults (particularly the elderly), but higher rates of hospitalizations requiring intensive care are observed in infants than in older children - the reasons for these differences are unknown. ACE2 is expressed in several adult tissues and cells, including alveolar type 2 cells of the distal lung epithelium, but expression at other ages is largely unexplored. Here we show that ACE2 transcripts are expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood. Notably, the repertoire of cells expressing ACE2 protein in the mouse lung and airways shifts during key phases of lung maturation. In particular, podoplanin-positive cells, which are likely alveolar type I cells responsible for gas exchange, express ACE2 only in advanced age. Similar patterns of expression were evident in analysis of human lung tissue from over 100 donors, along with extreme inter- and intra-individual heterogeneity in ACE2 protein expression in epithelial cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection, is dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 inhibitor Noxa; in young individuals, MCL-1 inhibition is sufficient to trigger apoptosis in lung epithelial cells and may thus limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 disease severity across lifespan and advance our understanding of the regulation of ACE2 and cell death programs in the mammalian lung. Furthermore, our work provides the framework for translation of apoptosis modulating drugs as novel treatments for COVID-19.

The Dynamic Expression of Potential Mediators of Severe Acute Respiratory Syndrome Coronavirus 2 Cellular Entry in Fetal, Neonatal, and Adult Rhesus Monkeys

“…In COVID-19 patients, SARS-CoV-2 was reported to be detected in feces, suggesting the fecal–oral transmission ( Wu Y. et al, 2020 ). The expression of ACE2 exhibits heterogeneity; it was reported that ACE2 gene expression in the nasal epithelium and the lung airways was lower in children than in adults ( Bunyavanich et al, 2020 ; Saheb Sharif-Askari et al, 2020 ) and that ACE2 mRNA is expressed in the lungs and trachea shortly after birth, downregulated during childhood, and expressed at high levels in late adulthood again in alveolar epithelial cells ( Inde et al, 2020 ). Considering the high viral susceptibility and frequent defecation in infants, there should be more careful nursing measures for this population under COVID-19 risk.…”

“…ACE2 is a human homology of ACE ( Tipnis et al, 2000 ). The expression of ACE2 is dynamically changed with age; it was reported that ACE2 mRNA is expressed in the lungs and trachea shortly after birth, downregulated during childhood, and expressed at high levels in late adulthood again in alveolar epithelial cells ( Inde et al, 2020 ). Other potential receptors related to coronavirus include DPP4 , ANPEP , ENPEP , CD209 , and CLEC4G ( Bassendine et al, 2020 ; Qi et al, 2020 ).…”

SARS-CoV-2 Infection of Airway Epithelial Cells

“…In aged COVID-19 patients, the ability to eliminate the virus is impaired and proinflammatory response is augmented ( 64 ). The weakened epithelial barrier function and excessive reactive oxygen species production might exaggerate host damage by SARS-CoV-2 in the elderly ( 65 66 ).…”

The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer’s Disease and Aging: A Review of Knowledge

“…The viral infection has been observed by applying SARS-CoV-2 particles from nasopharyngeal aspirate of a human COVID-19 patient, on ex-vivo cultures of respiratory tract mucosae and in-vitro cultures of alveolar epithelial cells from healthy human donors [ 19 ]. In human biopsies, SARS-CoV-2 has been detected by immunohistochemistry in all differentiated cell types of the airway mucosa and of the alveolar epithelium, aging being related with increased ACE2 protein expression and decreased apoptosis effectors [ 30 ]. Its replication period is 2–4 days in both airway- and alveolar tissues [ 19 ].…”