Pathophysiological conditions induced by SARS-CoV-2 infection reduce ACE2 expression in the lung

Area of Science:

• Pulmonary Medicine
• Virology
• Cell Biology

Background:

• SARS-CoV-2 infects lungs, with COVID-19 progression influenced by underlying conditions like interstitial pneumonia.
• Understanding the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) is crucial for COVID-19 patient outcomes.

Purpose of the Study:

• To investigate ACE2 and TMPRSS2 expression in idiopathic pulmonary fibrosis (IPF) and a mouse model of usual interstitial pneumonia (UIP).
• To analyze changes in ACE2 and TMPRSS2 expression under viral infection and antifibrotic treatment conditions.

Main Methods:

• Histopathological and biochemical analysis of human IPF specimens and a mouse model of induced UIP (iUIP).
• Assessment of ACE2 and TMPRSS2 expression in precision-cut lung slices (PCLS) under various conditions, including Poly(I:C) stimulation, interferon/cytokine exposure, hypoxia, and nintedanib treatment.

Main Results:

• ACE2 expression decreased with acute lung inflammation but increased in abnormal lung epithelium in the iUIP model, with expression also noted in metaplastic epithelial cells.
• Poly(I:C), interferons, cytokines, and hypoxia (via HIF1α) decreased ACE2 expression in PCLS from the iUIP model.
• Nintedanib, an antifibrotic agent, reduced ACE2 expression in invasive epithelial cells. Patients with IPF exhibit high ACE2 expression, but viral infection and antifibrotic treatments decrease ACE2 and TMPRSS2 expression.

Conclusions:

• While IPF patients have high ACE2 expression, potentially increasing SARS-CoV-2 risk, viral infection-induced immune responses and antifibrotic agents decrease ACE2 and TMPRSS2 expression.
• These modulations in receptor expression suggest a potential development of resistance against SARS-CoV-2 infection in certain pathophysiological contexts.