Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

Abstract

The new coronavirus (SARS-CoV-2) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.

Keywords: ACE2; Co-receptor; Coronaviruses; Macrophage; SARS-CoV-2; scRNA-seq.

Fig. 1

The expression profiles of ACE2 in 13 human tissues. The single cell expression maps of ACE2 in lung, liver, stomach, ileum, rectum, colon, blood, bone marrow, spleen, esophagus, kidney, skin and eye. ACE2 is expressed in lung AT2 (Alveolar cells Type2), liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs (enterocytes), rectum ECs, stomach epithelial cells, and kidney proximal tubules. None of the ACE2 transcripts was found in bone marrow and blood. PMCs, pit mucous cells; GMCs, antral basal gland mucous cells; PCs, proliferative cells in stomach and Paneth cells in ileum; EECs, enteroendocrine cells; Gs, goblet cells; PROs, progenitor cells; SCs, stem cells; TAs, transient amplifying; EECs, enteroendocrine cells; RPEs, retinal pigment epithelium.

Fig. 2

Pearson correlation coefficients between the curated ssRNA viral receptors and membrane proteins. The warm colors mean positive correlation, and the cold colors mean negative correlation. The stars represent the correlation coefficients greater than 0.8. ANPEP, ENPEP and DPP4 show highest correlation with ACE2.

Fig. 3

Cell-cell interactions between cell types in 8 tissues expressing ACE2. (A) The cell-cell interaction analysis was conducted by CellPhoneDB. Cell types are nodes and interactions are edges. Red nodes indicate major cell types expressing ACE2 in each tissue. Size of cell type is proportional to the total number of interactions with the red nodes. (B) The cytokines that connected ACE2-expressing cells and the macrophages. Macrophages expression receptors and ACE2-expressing cells express ligands.

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