Imbalanced host response to SARS-CoV-2 drives development of COVID-19
Authors: Blanco-Melo et al. Link to paper: https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00985.pdf
Journal/ Pre-Print: Cell
Key Words: Type I IFN, ISGs, chemokines, SARS-CoV2, RNAseq
1. The transcriptional response to SARS-CoV2 is distinct in comparison to other respiratory viruses
2. At low MOI (MOI = 0.2), SARS-CoV2 infection does not induce a strong type I or type III interferon response, whilst at high MOI (MOI = 2), SARS-CoV2 infection leads to significant induction of IFN.
3. Imbalanced limited IFN response and robust expression of inflammatory cytokines/chemokines caused by SARS-CoV-2 infection are likely to play a role in the recruitment of cells to the lung and the activation of the adaptive immune response.
The transcriptional response to infection with SARS-CoV2 is investigated in vitro (cell lines and primary cells), in vivo (ferrets) and ex vivo (lung tissue from COVID19 patients) and compared to uninfected. They also compare SARS-CoV2 with other respiratory viruses including SARS-CoV1 and IAV. Overall, SARS-CoV2 fails to induce a robust type I/III interferon response even in cells permissive to viral replication, although a subset of ISGs is induced independently of IFN signalling. In contrast, SARS-CoV2 constantly induces the expression of high levels of inflammatory chemokines. Further, they detect similar imbalanced immune response in SARS-CoV-2 infected ferrets and the serum in a cohort of 24 SARS-CoV2+ patients.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19: suppressed IFN response and robust cytokine and chemokine response
Understand the virology and/or cell biology of SARS-CoV2/COVID19: potential IFN antagonist
Clinical symptoms and pathogenesis of SARS-Cov2/COVID19: a viral-induced imbalanced immune response as a potential cause of COVID19
Develop diagnostic tools for SARS-CoV2/COVID19: potential unique transcription profile and leukocyte activity
Treat of SARS-CoV2/COVID19 positive individuals: immunomodulation drugs and anti-inflammatory drugs
· In silico study / bioinformatics study: Quantitative RNA seq analysis
· In vitro study: Cell culture
· In vivo study: Ferret
· Patient Case study
Strengths and limitations of the paper
Novelty: First detailed comparison of the transcriptional response to SARS-CoV2 to other respiratory viruses in multiple experimental systems.
Standing in the field: The conclusions fit well with other recent data looking at the cellular immune response to SARS-CoV2, although some other literatures are suggesting a less robust cytokine response due to viral immune suppression.
Appropriate statistics: Yes, mostly. Although some sample numbers are low (n=2 in some groups for the ferret in vivo experiments and the human lung samples)
Viral model used:
- SARS-related coronavirus 2 (SARS-CoV-2), USA-WA1/2020 (NR-52281)
- Influenza A/Puerto Rico/8/1934 (H1N1)
- Influenza A/Texas/71/2017 (H3N2)
Recombinant GFP-expressing human respiratory syncytial virus (RSV), strain A2 (§)
- eGFP/ GLuc-expressing human parainfluenza virus 3
Translatability: Not immediately, but this paper presents some evidence that blocking inflammatory pathways using existing drugs such as tocilizumab and anakinra could be beneficial for the treatment of COVID19 and suggests further investigation into this could is warranted.
- Did not attempt to identify the viral component that suppress IFN response in infected cells.
- Low MOI infection is used to show less IFN response in SARS-CoV-2 infection while all other viruses were used at high MOI level.
- Only looked at the robustness of chemokine production but not its subsequent function.