Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Abstract

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Single-Cell Expression Landscape of SARS-CoV-2 Receptor ACE2 and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients

“…Future studies interrogating larger and more diverse cohorts will provide more power to analyze the expression of SARS-CoV-2 factors by LUAD stage or across histological subtypes, as well as in individual patients and at the single-cell level. Furthermore, it is conceivable that expression patterns of ACE2 and SARS-CoV-2 host proteases in malignancies of the upper airways may be different from the patterns observed in LUAD (i.e., a cancer of the peripheral lung), and this is supported by recent studies showing the expression of ACE2 in secretory cells (such as those in the upper airway) [47,48], which we also noted in our limited cohort. Additional studies in more diverse lung cancer cohorts are thus needed to interrogate these suppositions.…”

Sex differences in immunological responses to COVID-19: a cross-sectional analysis of a single-centre cohort

“…4,5 Greater expression of virus entry factors (angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) in airway secretory cells and alveolar type 2 cells may explain the greater cytokine levels in male patients. 6 However, we found similar viral titres (Ct values) between males and females, suggesting that increased viral burden does not completely explain the differences in host response between males and females. In addition to differences in cytokine levels between sexes, poor T cell response is associated with worse disease outcome in male patients, but not in female patients.…”

COVID-19 and the liver: What do we know so far?

“…The pathogenic properties of SARS-CoV-2 depend on the binding of viral spike proteins to the host angiotensin-converting enzyme 2 (ACE-2) receptors, which allows the virus to enter the target cells along with priming by the host transmembrane serine protease 2 (TMPRSS2)[ 12 - 14 ]. The ACE-2-TMPRSS2 is expressed in the ileum, liver, lung, nasal mucosa, bladder, testis, prostate, and kidney (in that order)[ 14 - 17 ]. SARS-CoV-2 binding to ACE-2 receptors in the upper respiratory tract is the primary site of replication and entry to the body[ 14 ].…”