Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene 3 expression in the airway epithelium
Authors: Sajuthi, et al Link to paper: https://www.biorxiv.org/content/10.1101/2020.04.09.034454v1.full.pdf+html
Journal/ Pre-Print: bioRxiv
Key Words: ACE2, TMPRSS2, Th2 inflammation
1. ACE2 is expressed in basal/early secretory cells, ciliated cells, and secretory cells while TMPRSS2 is expressed by all epithelial cell types
2. Identification of T2 cytokine inflammation as major driver for ACE2 downregulation and TMPRSS2 upregulation
3. Coronavirus infection (normal circulating viruses) is associated with increased cytotoxic gene signature
Sajuthi et al aimed to explore the role of genetics in regulating the levels of ACE2, the SARS-CoV-2 receptor and TMPRSS2, a protease that cleaves the spike to allow efficient viral entry. They analysed the nasal airway transcriptome of healthy and asthmatic children, identifying expression quantitative trait loci (eQTL) which vary across world populations. TMPRSS2 is shown to be induced by IL-13, and interferon response to respiratory viruses increases ACE2 expression. Specifically, responses to coronaviruses upregulate IL-6 and cytotoxic gene signatures. Their findings reveal mechanisms likely influencing infectivity and clinical outcomes of SARS-CoV-2.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19:
Coronaviruses induce interferon and cytotoxic gene programs & they explored the regulation of ACE2 & TMPRSS2 in different cell types of the airway
Understand the virology and/or cell biology of SARS-CoV2/COVID19
Shows Type 2 immunity and interferon response impact gene expression in the lung (increased TMPRSS2 and ACE2 respectively), which may influence viral entry. They also compared the immune response of CoV with other respiratory viral infections to identify CoV-specific host responses
· In silico study / bioinformatics study
· In vitro study
· Clinical Cohort study
Strengths and limitations of the paper
Novelty: Th2 immunity increases TMPRSS2 but decreases ACE2 expression in vitro and in children
Standing in the field: There is previous literature suggesting ACE2 is IFN-inducible. The authors claims are minimal, so they are not controversial.
Appropriate statistics: I would like further input from someone familiar with eQTL analysis, (Agree: CVA) Statistical methods described in detail; data cleaned up
Viral model used: Circulating coronavirus infection in children, CoV subfamily infections
Translatability: It is unclear how these findings in children will relate to severity of disease in adults. The strongest effect is interferon inducing ACE2, which was already known. Measurement of blood eosinophil levels as proxy for investigating association between airway T2 inflammation & outcome of COVID-19 infection
Main limitations: The study was of nasal airway epithelium in children so it is unclear how these results will relate to adults and other sites of infection deeper in the lungs or elsewhere in the body. Because the two genes of interest are not regulated similarly, it is unclear how type2 immunity with affect SARS-CoV2 infection.
- The data has been extracted from a dtabase for asthmatic children, that would be TH2 biased already