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Authors: Benjamin Israelow et al.

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.27.118893v1

Journal/ Pre-Print: bioRxiv

Tags: Immunology/Immunity, Inflammation

Research Highlights

1. Development of a SARS-CoV-2 mouse model using adeno-associated virus (AAV)- mediated expression of hACE2 in the respiratory tract, which supports viral replication and antibody production.

2. Interferon stimulated genes (ISGs) and inflammatory responses are upregulated in SARS-CoV-2 infected AAV-hACE2 mice and closely resemble characteristics of COVID-19 in humans.

3. Type I interferons are unable to control SARS-COV-2 replication and viral clearance, but lead to recruitment of proinflammatory cells in the lungs.

Summary

A mouse model of COVID19 was developed using AAV-mediated expression of human ACE2 in the respiratory tract, which supports productive SARS-CoV-2 infection. Infected mice had acute infiltration of innate and adaptive immune cells to the lungs and developed specific neutralising antibodies. Transcriptomic analysis showed robust expression of cytokines and ISGs, with many genes overlapping with those upregulated in the lungs of COVID-19 patients. Infection of AAV-hACE2 mice lacking IFNAR1 or IRF3/7 clearly showed that type I IFN signalling is important for driving the recruitment and activation of immune cells to the lungs but has little effect on viral clearance.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

Develop diagnostic tools for SARS-CoV2/COVID19

(study develops a mouse model which can be used as a platform for rapidly testing prophylactic and therapeutic strategies against SARS-CoV-2 infection)

Study Type

· In vivo study (mouse)

Strengths and limitations of the paper

Novelty: Development of a novel, broadly available mouse model which expresses the human ACE2 receptor in the respiratory tract and thereby overcomes the limitation that mice don’t support SARS-CoV-2 cellular entry. The method described here has the added advantage that it can be used to study SARS-CoV-2 infection in mice of different genetic backgrounds, age and transgenics. This is the first study to look at SARS-CoV-2 mice in IFNAR1 and IRF3/7-deficient mice.

Standing in the field: Gene expression in mouse model concordant with results from patient lung autopsy from Blanco-Melo et al. Consistent with other studies, type I interferon signalling was important for recruitment and activation of proinflammatory immune cells. This contradicts the therapeutic use of IFN against COVID-19 which is promoted by other reports. Two transgenic hACE2 mice lines have been recently published.

Appropriate statistics: No information on the statistical tests used is provided. In addition, there is no information on the number of mice per group when only mean plus error bars are shown.

Viral model used: original SARS-CoV-2 (isolate USA-WA1/2020)

Translatability: The developed mouse model can be used for safety and efficacy analysis in drug and vaccine studies. Revealing a pathological role of type I IFN in respiratory inflammation might change its current promoted use as a therapeutic treatment; however, more studies are needed to evaluate this.

Main limitations: Experimental groups contain variable number of mice, some only contain one or two mice making certain data (e.g. Figure 1C, Figure 1F, the IRF3/7 KO group in Figure 3) difficult to interpret in parts.

Lack of information on statistical tests.

Throughout the paper, it is sometimes unclear exactly what ‘control’ is referring to in each figure.

In Figure 2D (RNAseq analysis), there is large variability in the expression of genes within the groups (e.g. the two infected control mice and the two infected AAV-hACE2 mice) which is not discussed.

The expression levels of hACE2 in the lungs is not shown, besides immunofluorescence staining in one mouse (Extended Data Fig 1A), which is from 20 d.p.i. when all experiments were performed 14 d.p.i.. hACE2 expression should be quantified, also to show variability between mice. Flow cytometry/immunofluorescence to show which cells in the lung express hACE2 is also missing. This would be important information if this is to be used as a model for the human disease.

Transcription analysis of uninfected AAV-hACE2 is missing which would show what effect delivery of hACE2 has on the expression of ISGs and cytokines.

The data showing the effect of IFNAR1 or IRF3/7 KO on viral replication in Figure 3A and 3B are not conclusive due to the low number of mice per group.