Cigarette smoke triggers increased ACE-2 expression in the lung

Smith et al., 2020. Graphical Abstract

Smith et al., 2020. Graphical Abstract

Smith et al., 2020. Graphical Abstract

Similar to related coronavirus that emerged in 2003 (1), SARS-CoV-2 enters human cells by binding to the extracellular domain of Angiotensin Converting Enzyme 2 (ACE 2) (2, 3). ACE 2 normally functions in the renin-angiotensin system (RAS) by cleaving the vasoconstrictive hormone angiotensin-II into the vasodilator angiotensin (4). Sequestration of ACE 2 by coronavirus dysregulates the RAS pathway, contributing to morbidity (5). Additionally, modulation of ACE 2 levels is capable of influencing disease progression, e.g. mice engineered to express human ACE 2 mRNA exhibited short survival time following coronavirus exposure (6). Thus, suggesting that regulation of ACE 2 expression likely has a significant effect on SARS-CoV-2 susceptibility.

Smith, et al., showed that cigarette smoke causes a dose-dependent upregulation of ACE-2 in rodent and human lungs. Using single-cell sequencing data, they demonstrated that ACE 2 is expressed in a subset of epithelial cells that line the respiratory tract, including goblet cells, club cells, and alveolar type 2 cells. They showed that cigarette smokers harbor consistently higher levels of ACE-2 in their lungs compared to non-smokers. In contrast, quitting smoking causes a decrease in lung ACE-2 levels. The overabundance of ACE 2 in the lungs of smokers may partially explain why smokers are significantly more likely to develop severe SARS-CoV-2 infections that require aggressive medical interventions (8).

Upregulation of ACE-2 in smokers could be a protective mechanism to prevent lung damage in smokers. However, when a smoker is exposed to SARS-CoV-2 higher ACE-2 expression may facilitate increased viral entry and replication. Taken together, these results may partially explain why smokers are particularly likely to develop severe SARS-CoV-2 infections, and they suggest that quitting smoking could lessen coronavirus susceptibility.

Journal Article:  Smith, J. C., et al., (2020). Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Developmental Cell

References

  1. Li, W. et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450454 (2003).
  2. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
  3. Hoffmann, M. et al.SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020) doi:10.1016/j.cell.2020.02.052.
  4. Zhu, N. et al.A Novel Coronavirus from Patients with Pneumonia in China, 2019.  NEJM 382, 727–733 (2020).
  5. Kuba, K. et al.A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus – induced lung injury. Nature Medicine11, 875– 879 (2005).
  6. McCray, P. B. et al.Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus. Journal of Virology 81, 813–821 (2007).
  7. Wu, Z. & McGoogan, J. M. Characteristics of and Important Lessons From the Coronavirus  Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From  the Chinese Center for Disease Control and Prevention. JAMA (2020) doi:10.1001/jama.2020.2648.
  8. Guan, W.-J. et al. Clinical Characteristics of Coronavirus Disease 2019 in China. NEJM (2020) doi:10.1056/NEJMoa2002032.

Article by Naffesa Al Sheikh