Distinct Inductions of and Responses to Type I and Type III Interferons Promote Infections in Two SARS-CoV-2 Isolate

Authors: Fu Hsin, Tai-Ling Chao, Yun-Rui Chan, Han-Chieh Kao, Wang-Da Liu, Jann-Tay Wang, Yu-Hao Pang, Chih-Hui Lin, Ya-Min Tsai, Jing-Yi Lin, Sui-Yuan Chang, Helene Minyi Liu

Link to paper: https://www.biorxiv.org/content/10.1101/2020.04.30.071357v1

Journal/ Pre-Print: bioRxiv

Tags: Cell Biology, Clinical, Immunology/Immunity, Molecular biology, Virology

Research Highlights

1. SARS-Cov2 infection induces IFN-I/III production in Calu-3 cells

2. Chemical inhibition of TBK1, a signalling molecule downstream of many pattern recognition receptors, drastically inhibits IFN-β and IFN-λ induction.

3. RNA extracted from SARS-CoV2 infected cells induces minimal innate immune activation.

Summary 

In this study, Hsin et al isolated SARS-CoV2 from 2 Chinese patients and used the isolated virus to infect lung epithelium carcinoma cell lines in order to investigate the antiviral interferon response against SARS-CoV2. It was shown that Calu-3 cells were the only cells tested responding with a type I & type III interferon response against SARS-CoV2 infection, and that this induction was TBK1-dependent but mostly RNA recognition-independent. Post-infection treatment of infected cells with IFNs did not lower viral titres and conversely lead to increase in ACE2 expression. Neutralisation assay showed a patient with slow viral clearance also had poorly neutralising antibodies compared to a patient who rapidly cleared the virus.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

Understand the virology and/or cell biology of SARS-CoV2/COVID19

Inhibit of SARS-CoV2/COVID19

Study Type

· In vitro study

· Patient Case study

Strengths and limitations of the paper

Novelty:

- Post-infection treatment with interferons appears to be ineffective. This helps to understand underlying signalling mechanisms of SARS-CoV2 infections.

- Preliminary data investigating viral ligands that trigger production of IFNs.

Standing in the field: Supports the study of Lokugamage (March 2020) that IFN-pre-treatment lowers SARS-CoV2 titres.

Appropriate statistics: Yes

Viral model used: SARS-CoV2 isolates from 2 patients used for infection of Calu-3 cells, MEFs, A549 cells, Huh7 cells

Translatability: Potential usage of TBK1-activators for increased IFN response in patients & reduction of viral titres

Main limitations:

· Perform MAVS knockdown additionally in VeroE6 cells or Calu-3 cells & perform experiments in cell types that can be infected (Huh7 & A549 cells did not show high SARS-CoV2 infection rates)

· Little work has been done into clarifying what could be the ligand for triggering innate immune activation.

· An in vivo model would be helpful to better understand the antiviral response and effect of post-infection treatment with IFN on non-infected cells

· It would be of interest to determine viral sensors that are activated upon SARS-CoV2 infection as RNA sensors appear not to be involved

· Conclusions drawn on how antibody potency could effect disease progression are based on only 2 patients.