Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation: A physio-pathological theory

Med Hypotheses. 2021 Jan;146:110412. doi: 10.1016/j.mehy.2020.110412. Epub 2020 Nov 23.


The Corona Virus Disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) requires a rapid solution and global collaborative efforts in order to define preventive and treatment strategies. One of the major challenges of this disease is the high number of patients needing advanced respiratory support due to the Acute Respiratory Distress Syndrome (ARDS) as the lung is the major - although not exclusive - target of the virus. The molecular mechanisms, pathogenic drivers and the target cell type(s) in SARS-CoV-2 infection are still poorly understood, but the development of a "hyperactive" immune response is proposed to play a role in the evolution of the disease and it is envisioned as a major cause of morbidity and mortality. Here we propose a theory by which the main targets for SARS-CoV-2 are the Type II Alveolar Epithelial Cells and the clinical manifestations of the syndrome are a direct consequence of their involvement. We propose the existence of a vicious cycle by which once alveolar damage starts in AEC II cells, the inflammatory state is supported by macrophage pro-inflammatory polarization (M1), cytokines release and by the activation of the NF-κB pathway. If this theory is confirmed, future therapeutic efforts can be directed to target Type 2 alveolar cells and the molecular pathogenic drivers associated with their dysfunction with currently available therapeutic strategies.

Keywords: AEC-II; ARDS; Alveolar epithelial cell type 2; COVID-19; COVID-19 pathogenesis; NF-kB pathway activation; SARS-CoV-2.

MeSH terms

  • Alveolar Epithelial Cells / immunology*
  • Alveolar Epithelial Cells / pathology
  • Alveolar Epithelial Cells / virology*
  • Angiotensin-Converting Enzyme 2 / physiology
  • COVID-19 / etiology
  • COVID-19 / immunology*
  • COVID-19 / virology*
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / pathology
  • Heparin, Low-Molecular-Weight / therapeutic use
  • Humans
  • Inflammation / immunology
  • Inflammation / pathology
  • Liquid Ventilation
  • Macrophages / immunology
  • Macrophages / pathology
  • Models, Biological*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / immunology*
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Pandemics
  • Pulmonary Surfactants / therapeutic use
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / immunology
  • Respiratory Distress Syndrome / virology
  • SARS-CoV-2* / immunology
  • SARS-CoV-2* / pathogenicity
  • Signal Transduction / immunology


  • Heparin, Low-Molecular-Weight
  • NF-kappa B
  • Pulmonary Surfactants
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2