Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

Abstract

58Respiratory failure is the leading cause of COVID-19 death and disproportionately 59 impacts adults more than children. Here, we present a large-scale snATAC-seq dataset 60 (90,980 nuclei) of the human lung, generated in parallel with snRNA-seq (46,500 nuclei), 61 from healthy donors of ~30 weeks, ~3 years and ~30 years of age. Focusing on genes 62 implicated in SARS-CoV-2 cell entry, we observed an increase in the proportion of 63 alveolar epithelial cells expressing ACE2 and TMPRSS2 in adult compared to young 64 lungs. Consistent with expression dynamics, 10 chromatin peaks linked to TMPRSS2 65 exhibited significantly increased activity with age and harbored IRF and STAT binding 66 sites. Furthermore, we identified 14 common sequence variants in age-increasing peaks 67 with predicted regulatory function, including several associated with respiratory traits and 68 TMPRSS2 expression. Our findings reveal a plausible contributor to why children are 69 more resistant to COVID-19 and provide an epigenomic basis for transferring this 70 resistance to older populations. 71 72 73 74

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

“…Human lung tissue demonstrated low levels of ACE2 expression in infants, children, and adult samples ( Fig S5). These data are broadly consistent with results of a single-nucleus RNA-seq (snRNA-seq) study of infants, children and adults up to age 30 that was reported while this manuscript was being finalized, though notably that study did not show tissue validation of their findings (16).…”

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…Collectively, these results consistently indicate that the human placental tissues negligibly co-express ACE2 and TMPRSS2. This reduced expression contrasts with the high expression of ACE2 and TMPRSS2 in nasal goblet and ciliated cells within the human airways, lungs, and gastrointestinal tract, which are targeted during COVID-19 [69][70][71]. Therefore, our results suggest that vertical transmission of SARS-CoV-2 is unlikely to occur unless facilitated by other concomitant pathological conditions resulting in a breach of the maternal-fetal crosstalk.…”

Single-cell transcriptomic atlas of primate cardiopulmonary aging

“…66 However, the alteration of ACE2 expression during aging is still controversial. [66][67][68] In this study, we present the first comparative single-nucleus/single-cell sequencing atlas of old versus young primate lung and cardiovascular tissues, revealing that ACE2 expression was upregulated in a both age-dependent and cell type-specific manner. The agingassociated upregulation of ACE2 was further confirmed by multiple assays, such as in-depth bulk RNA-seq, RT-qPCR, RNA-ISH, and immunostaining in various tissues.…”

“…Cell types were identified according to the expression of canonical marker genes for each cluster (Supplementary information, Table S2). 31,67,85,99,100 Dimensionality reduction was performed with the "RunUMAP" function and the resultant data were visualized with the "DimPlot" function.…”