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HGNC Genes

SARS-CoV-2 proteins

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

    Authors: Zintis Inde; Clarence Yapp; Gaurav N Joshi; Johan Spetz; Cameron Fraser; Brian Deskin; Elisa Ghelfi; Chhinder Sodhi; David Hackam; Lester Kobzik; Ben Croker; Douglas Brownfield; Hongpeng Jia; Kristopher A. Sarosiek; Paige D. Hall; Maud Jansen; Kumaran Shanmugarajah; Jessica S. Donington; Florian Krammer; Daved Fremont; Andrzej Joachimiak; Yoshihiro Kawaoka; Vera Tesic; Maria Lucia Madariaga; Patrick C Wilson; Martin Pettersson; Mattew R. Reese; Thomas Rogers; Michelle I Rossulek; Jean G Sathish; Claire Steppan; Martyn Ticehurst; Lawrence W. Updyke; Yuao Zhu; Jun Wang; Arnab K Chatterjee; Andrew D Mesecar; Annaliesa S. Anderson; Charlotte Allerton

    doi:10.1101/2020.09.13.276923 Date: 2020-09-13 Source: bioRxiv

    Angiotensin-converting enzyme 2 ( ACE2 HGNC) maintains cardiovascular and renal homeostasis MESHD but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) MESHD, the causal agent of novel coronavirus disease 2019 MESHD ( COVID-19 MESHD)1. COVID-19 MESHD disease severity, while highly variable, is typically lower in pediatric patients than adults (particularly the elderly), but increased rates of hospitalizations requiring intensive care are observed in infants than in older children. The reasons for these differences are unknown. To detect potential age-based correlates of disease severity, we measured ACE2 HGNC protein expression at the single cell level in human lung tissue specimens from over 100 donors from [~]4 months to 75 years of age. We found that expression of ACE2 HGNC in distal lung epithelial cells generally increases with advancing age but exhibits extreme intra- and inter-individual heterogeneity. Notably, we also detected ACE2 HGNC expression on neonatal airway epithelial cells and within the lung parenchyma. Similar patterns were found at the transcript level: ACE2 HGNC mRNA is expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood in alveolar epithelial MESHD cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection MESHD, is also dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1 HGNC. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 HGNC inhibitor Noxa HGNC; in juveniles, MCL-1 HGNC inhibition is sufficient to trigger apoptosis in lung epithelial cells - this may limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 MESHD disease severity across lifespan and advance our understanding of the regulation of ACE2 HGNC and cell death programs in the mammalian lung. Furthermore, our work provides the framework for potential translation of apoptosis modulating drugs as novel treatments for COVID-19 MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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