Dysregulation of endocytic machinery and ACE2 in small airways of smokers and COPD patients can augment their susceptibility to SARS-CoV-2 (COVID-19) infections

Am J Physiol Lung Cell Mol Physiol. 2021 Jan 1;320(1):L158-L163. doi: 10.1152/ajplung.00437.2020. Epub 2020 Nov 11.


Lungs of smokers and chronic obstructive pulmonary disease (COPD) are severely compromised and are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attack. The dangerous combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L, and lysosomal associated membrane protein-1 (LAMP-1) as lysosome markers in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I or GOLD stage II COPD, of which 9 were current smokers with COPD (COPD-CS) and 10 were ex-smokers with COPD (COPD-ES), 10 were normal lung function smokers, and 10 were never-smoking normal controls. Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Furthermore, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1-stained areas per total area of epithelium or subepithelium, using Image ProPlus v7.0 software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.

Keywords: ACE2; COPD; COVID-19; SARS-CoV-2; electronic cigarettes; smoking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism*
  • COVID-19 / pathology*
  • Cathepsin L / metabolism
  • Cross-Sectional Studies
  • Disease Susceptibility
  • Humans
  • Lung / pathology
  • Lysosomal Membrane Proteins / metabolism
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • SARS-CoV-2
  • Smokers
  • Smoking / pathology*
  • Transport Vesicles / metabolism*
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism
  • rab7 GTP-Binding Proteins


  • LAMP1 protein, human
  • Lysosomal Membrane Proteins
  • Vesicular Transport Proteins
  • early endosome antigen 1
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • CTSL protein, human
  • Cathepsin L
  • rab GTP-Binding Proteins