Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits a broad tissue tropism that underpins the multisystem nature of coronavirus disease 2019 (COVID-19). Understanding viral entry mechanisms, primarily mediated by the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2), is essential for appreciating how the virus targets specific host tissues. This section examines SARS-CoV-2 tropism in the respiratory epithelium, endothelium, gastrointestinal tract and nervous system, drawing on peer-reviewed evidence to evaluate receptor distribution and cellular permissiveness.
Respiratory Epithelium
SARS-CoV-2 displays strong tropism for the respiratory epithelium, where ACE2 is expressed on the apical surface of ciliated cells and type II pneumocytes. Viral entry is facilitated by TMPRSS2-mediated cleavage of the spike protein, enabling efficient membrane fusion. In primary human airway epithelial cultures, SARS-CoV-2 preferentially infects ciliated cells, leading to impaired mucociliary clearance and subsequent inflammation (Hoffmann et al., 2020). This tropism accounts for the predominance of upper and lower respiratory symptoms observed clinically.
Endothelium
Endothelial tropism has been demonstrated through detection of viral particles within vascular endothelial cells and associated endotheliitis. ACE2 expression on endothelial cells permits direct infection, potentially contributing to microvascular dysfunction and thrombosis. Post-mortem analyses have revealed SARS-CoV-2 within endothelial cells of multiple organs, accompanied by inflammatory infiltrates and apoptosis (Varga et al., 2020). Consequently, endothelial infection may exacerbate systemic coagulopathy and organ ischaemia beyond direct parenchymal damage.
Gastrointestinal Tract
The gastrointestinal tract represents another permissive site due to high ACE2 expression on enterocytes of the small intestine and colon. Viral RNA and replicating virions have been recovered from faecal samples and intestinal biopsies, indicating active replication independent of respiratory involvement. This tropism may underlie gastrointestinal manifestations such as diarrhoea and supports the potential for faecal-oral transmission under specific conditions (Xiao et al., 2020). Receptor abundance in the ileum exceeds that in the respiratory tract, explaining prolonged viral shedding observed in some patients.
Nervous System
Neurotropism of SARS-CoV-2 remains incompletely defined yet is supported by evidence of ACE2 expression in neurons and glial cells, particularly within the olfactory epithelium and brainstem. Cerebrospinal fluid detection of viral RNA and neuroimaging findings of encephalitis suggest direct central nervous system invasion, possibly via trans-synaptic spread from peripheral nerves. Nevertheless, the frequency and clinical significance of such events require further clarification, as neuroinvasion appears less consistent than respiratory or gastrointestinal infection (Song et al., 2021).
Conclusion
Collectively, these observations indicate that SARS-CoV-2 tropism extends well beyond the respiratory tract through utilisation of ACE2 and associated proteases. Recognition of endothelial, gastrointestinal and limited neural involvement informs therapeutic targeting and prognostic stratification. Continued investigation using primary tissue models remains necessary to refine understanding of tissue-specific pathogenesis.
References
- Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herler, G., Wu, N.-H., Nitsche, A., Müller, M.A., Drosten, C. and Pöhlmann, S. (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), pp. 271-280.
- Song, E., Zhang, C., Israelow, B., Lu-Culligan, A., Sprado, A., Skelly, A.N., Fischer, S., Mack, M., Santos, G.S., Balla, K., Fajardo, G., Alpert, T., Valdez, J., Glick, A., Stock, A., Oliveira, E., Silva, J., Benjamin, A., Pérez-Vargas, J., … and Iwasaki, A. (2021) Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal of Experimental Medicine, 218(3), e20202135.
- Varga, Z., Flammer, A.J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A.S., Mehra, M.R., Schuepbach, R.A., Ruschitzka, F. and Moch, H. (2020) Endothelial cell infection and endotheliitis in COVID-19. The Lancet, 395(10234), pp. 1417-1418.
- Xiao, F., Tang, M., Zheng, X., Liu, Y., Li, X. and Shan, H. (2020) Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology, 158(6), pp. 1831-1833.
