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Authors: Abigail Vanderheiden et al.,

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.19.105437v1

Pre-Print: BioRxiv

Tags: Cell Biology, Immunology/Immunity, Inflammation, Virology, Type I, III interferon

Research Highlights

1. SARS-CoV2 is released directionally from the apical but not basolateral surface of primary human airway epithelial cells (pHAE)

2. Transcriptional profiling of infected pHAE cells suggests NFkB (pro-inflammatory) and ATF4 (cellular stress pathway) as the dominating transcription factors in SARS-CoV-2 infection.

3. Complete lack of type I or III IFN induction in SARS-CoV-2-infected pHAE.

Summary

Primary human airway epithelial (pHAE) cells were cultured in an air-liquid interface system to mimic the polarised lung epithelium. When infected with SARS-CoV-2, pHAE cells release the virus directionally from the apical (externally facing) but not the basolateral surface. Bulk mRNA sequencing showed an NF-κB-driven pro-inflammatory signature in infected cells, as well as induction of genes involved in the unfolded protein response and epithelial to mesenchymal transition. Unexpectedly, there was a complete lack of type I or III interferon gene induction during SARS-CoV-2 infection in pHAE cells. Nonetheless, treatment with type I or III interferon, pre or post infection, reduced viral replication, suggesting a possible role for type I and III interferon as therapeutic options.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV-2/COVID19

Understand the virology and/or cell biology of SARS-CoV-2/COVID19

Study Type

· In vitro study

pHAE cells cultured so to create a polarised, pseudostratified epithelial layer were infected with SARS-Cov-2

Strengths and limitations of the paper

Novelty: The use of an in vitro lung epithelial tissue model. Showing the induction of cytokines and location of viral release in this model. Discovery that pHAE cells do not produce type I or III IFN in response to SARS-CoV-2 infection.

Standing in the field: SARS-CoV is known to antagonise interferon induction. Whether the same holds true for SARS-CoV-2 is under intense investigation, and this manuscript makes an important contribution to these efforts.

Appropriate statistics: Yes

Viral model used: SARS-CoV-2 strain, nCoV2019/WA

Translatability: low, but data set argues in favour of exploring interferon-based therapies.

Main limitations:

1. No positive viral infection control to show that pHAE cells are in fact capable of producing type I and III IFNs in other viral infections

2. There are no data yet to show that the production of type I/III IFNs from epithelial cells is important in COVID-19. The model used in the study does not include immune cells (e.g. alveolar macrophage or pDCs) that are known producers of type I IFN. In vivo these cells might compensate for and/or activate pHAE cells.

3. Minimal evidence of directionality of viral release (e.g. would be great to have cryo-EM figure showing release of virions for single surface).

4. No testing at protein level to look at up and down regulation of NF-κB induced cytokines.

5. No mechanism proposed for the inhibition of type I/III IFN in pHAE cells.