Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

Abstract

The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2.We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

“…3c, Supplementary Table 4). Among these 20 genes, the tumor suppressor DMBT1, a glycoprotein that has been shown previously to be highly expressed in ACE2 + AT2 cells 54 and can bind to SARS-CoV-2 spike proteins 55 , and the cartilage acidic protein 1 (CRTAC1), previously known to be downregulated significantly in COVID-19 patients with severe infection 56 , were upregulated in ACE2 + compared to ACE2-AT2 CLD cells (Fig. 3d).…”

Evaluation of Diagnostic Modalities for SARS-Cov-2: A Review Study

“…SARS-CoV-2 can also spread via other routes of infection (i.e., close contact) if the virus persists on surfaces; however, it is not clear whether these routes are required for the distribution of the virus. SARS-CoV-2 binds to ACE2 receptors on type II pneumocystis 25 during entry into cells. Several pieces of evidence suggest that SARS-CoV-2 might change over time, or simultaneously, there may be more than one strain of the virus in circulation.…”

Potential role of glycoprotein 340 in milder SARS-CoV-2 infection in children

“…This expression was also positively correlated with ACE-2 levels. Furthermore, a population of ACE-2-positive AT2 cells was identified to co-express viral pathogen and GP-340 receptor that is crucial for the host defense, thus suggesting a possible phenotypic target for the treatment of COVID-19 [ 13 ].…”

“…The results showed a higher content of GP-340 in the whole saliva of the youngest age group compared with the adult group, thereby suggesting a vital innate immunity factor present in children’s saliva [ 15 ]. One can speculate that since children have higher GP-340 along with lower ACE-2 receptors [ 13 ], they present a different response against SARS-CoV-2 infection compared with adults.…”