Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

Area of Science:

• Genetics
• Immunology
• Virology

Background:

• Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) uses host ACE2 and TMPRSS2 proteins for cell entry.
• Understanding the regulation of these entry factors is crucial for comprehending SARS-CoV-2 tropism and COVID-19 pathogenesis.

Purpose of the Study:

• To investigate the role of genetics and co-expression networks in regulating ACE2 and TMPRSS2 expression in the pediatric airway.
• To elucidate the impact of inflammation and viral infections on these host factors.

Main Methods:

• Analysis of nasal airway transcriptome data from 695 children.
• Identification of expression quantitative trait loci (eQTLs) for ACE2 and TMPRSS2.
• Examination of co-expression networks and the influence of inflammatory mediators like interleukin-13 (IL-13) and interferon response.

Main Results:

• Expression quantitative trait loci for ACE2 and TMPRSS2 were identified, with varying population frequencies.
• TMPRSS2 was found to be part of a mucus secretory network upregulated by type 2 (T2) inflammation via IL-13.
• Interferon response to viruses significantly upregulated ACE2 expression, an effect also observed at the protein level.
• Common coronavirus infections in children induced host responses including IL6 and ACE2 upregulation.

Conclusions:

• Genetic variations influence ACE2 and TMPRSS2 expression levels in the airway.
• Interleukin-13-driven T2 inflammation and viral interferon responses play significant roles in regulating SARS-CoV-2 entry factors.
• These findings provide insights into mechanisms affecting SARS-CoV-2 infectivity and COVID-19 clinical outcomes.