Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

I Hamming, W Timens, M L C Bulthuis, A T Lely, G J Navis, H van Goor, I Hamming, W Timens, M L C Bulthuis, A T Lely, G J Navis, H van Goor

Abstract

Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.

Copyright 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Figures

Figure 1
Figure 1
Normal lung tissue: overview (A) and larger magnification (B). Positive staining for ACE2 is clearly present on alveolar epithelial cells (arrow) and capillary endothelium (arrow‐head). Fibrotic lung tissue (C) and larger magnification (D). Positive staining for ACE2 is clearly present on type II cells (arrow). Cultured lung type II alveolar epithelial cells (A549) are strongly positive for ACE2 (E). Control section stained with anti‐ACE2 in the presence of the synthetic ACE2 peptide shows no staining of lung tissue (F)
Figure 2
Figure 2
Overview of oral mucosa (A). Strong staining is observed in vascular endothelium (arrow) and vascular smooth muscle cells (arrow‐head). Granular ACE2 staining is present in the basal layer of the epithelium. In the small intestine (ileum) (B), strong staining can be seen in the villous brush border (arrow), the muscularis mucosae (arrow‐head), and the muscularis propria (star). In a larger magnification of the submucosa (C), strong staining is present in vascular endothelium (arrow) and vascular smooth muscle cells (arrow‐head). In a larger magnification of the villi (D), abundant staining is seen on the brush border of the enterocytes (arrow). In the colon (E), ACE2 staining is present in endothelium and vascular smooth muscle cells from the blood vessels (arrow‐head) and in the muscular layers. Control section stained with anti‐ACE2 in the presence of the synthetic ACE2 peptide shows no staining in the small intestine (ileum) (F)
Figure 3
Figure 3
Skin tissue (A) with larger magnification (C, D). Staining is abundantly present in blood vessels/capillaries and in the basal layer of the epidermis (arrow) and hair follicles (arrow‐head). Eccrine glands also express ACE2 (B)
Figure 4
Figure 4
In the brain (A), ACE2 is expressed only in endothelium (arrow) and vascular smooth muscle cells. In the liver (B), Kupffer cells, hepatocytes, and the endothelium of sinusoids are negative. Luminal staining in bile ducts is occasionally observed (arrow‐head). Vascular endothelium (arrow) and smooth muscle cells are positive. In the spleen (C), ACE2 is not expressed in cells of the immune system. Vascular and red pulp sinus endothelium is positive. In the kidney (D), ACE2 is present in glomerular visceral (arrow) and parietal (arrow‐head) epithelium, in the brush border (short arrow) and cytoplasm of proximal tubular cells, and in the cytoplasm of distal tubules and collecting ducts

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