Alveolar early progenitors in the aged human lung have increased expression of ACE2 accompanied with genes involved in beta-amyloid clearance: Indication of SARS-CoV-2 also using soluble ACE2 in aged-lungs to enter ACE2-negative cells

Abstract

COVID-19 is the current pandemic caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2) that uses ACE2 protein on the cell surface. By analyzing publicly available datasets, I uncovered that alveolar early progenitors (AEP), a subset of the type-2 pneumocytes, showed increased ACE2 expression in the older lungs. AEPs co-express TMPRSS2, CTSL. Aged AEPgene expression signature suggested an active response to beta-amyloid-induced ACE2 shedding, to limit the intercellular beta-amyloid accumulation in otherwise healthy human lungs.Susceptibility of AEP to SARS-CoV2 and ACE2 secretory capacity of these cells makes aged human lung sensitive for rapid-infection, by a possible in-solution ACE2 binding and entry into ACE2-negative cells, thereby increasing the target cell diversity and numbers. Single-cell analysis of COVID19 patients with moderate and severe infections, clearly showed that severe infections showed SARS-CoV-2 transcript in ACE2-negative TMPRSS-negative but CTSLpositive cell types in their bronchoalveolar lavage fluid, validating in-solution ACE2-binding enabling infection. Since December 2019, SARS-CoV-2(COVID-19) infection, which was first reported in WuhanChina , has rapidly spread and turned into a worldwide pandemic, claiming as of May 25, 2020, more than 5.4 million infections with more than >344,000 deaths. COVID-19 has ~3-4% fatality rate (https://coronavirus.jhu.edu/map.html). COVID-19 virus belongs to the family of MER viruses, which causes infections in the human respiratory system leading to severe respiratory syndrome that can result in death. More importantly, the SARS-CoV-2 develops atypical pneumonia with a higher risk for older individuals or individuals with lung, heart, and kidney-related health issues (Shen et al., 2020), leading to a higher fatality rate accompanied by rapid progression of the respiratory syndrome and atypical pneumonia . SARS-CoV-2 binds to angiotensin-converting enzyme-2 (ACE2) binding followed by priming of spike protein S2 by transmembrane serine protease-2 (TMPRSS2) to enter the cells. Once internalized, Cathepsin L activates spike protein S, allowing the fusion of endosomal and viral membranes. A recent report has identified several epithelial cell subsets type-II pneumocyte, club cells, and ciliated cells in the lungs have ACE2, TMPRSS2 and CTSL expression. These are key genes for establishing COVID-19n infection(Hoffmann et al., 2020).Therapeutic interventions of SARS-CoV-2 needed a biological basis and possibly a mechanism of its severity. I used an analytical approach to integrate public datasets to answer the question, why the aged human population is at risk of severity and a higher fatality rate by SARS-CoV-2 ?The analysis is centered around the essential genes ACE2, TMPRSS2 and CTSL, that encodes the proteins implicated and shown to be responsible for entry to establishing the viral infection.The analysis focuses on isolating any subset of cells that are potentially altered in aged-human lungs to support SARS-CoV-2 and what is the nature of this...

CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function

“…The remaining DESeq2 normalized reads were then z score normalized. GO enrichment was performed as previously described ( 58 , 59 ). GOstats package ( 60 ) was used for conditional hypergeometric testing, and 15,772 expressed genes across WT and Cish −/− RNA-seq data were used as gene universe, whereas 752 differentially regulated genes were used as input genes.…”

“…Promoter sequences of these genes (−1000 bp, TSS, +100 bp) were used as the test set, and a 10-fold scramble sequence set of these test sequences was generated for the background set. Homer functions “homer2 known” with default settings were used for motif enrichment analysis as described previously ( 59 , 61 ). For all significantly enriched motifs, we determined whether the associated transcription factor was listed as a known substrate of ERK1/2, AKT1, or ERK1/2 and AKT1 with PhosphoSitePlus ( 34 ).…”