STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters
bioinformatics immunology/immunity inflammation virology
Authors: Robbert Boudewijns et al.
Link to paper: https://doi.org/10.1101/2020.04.23.056838
Journal/ Pre-Print: bioRxiv
Tags: Immunology, Inflammation, Transcriptomics, Virology
1. Showed that Syrian hamsters are highly permissive to SARS-CoV-2 compared to mice, suggesting its use as a pre-clinical model for SARS-CoV-2.
2. Demonstrated that STAT2 signaling is required to restrict systemic virus dissemination, but also drives severe lung injury.
3. Suggested Micro-CT as a sensitive way of assessing the lung pathology in hamsters.
This study compared and characterised the viral infection status of SARS-CoV-2 and associated pathology in mice (BALB/c and C57BL/6) and Syrian hamsters. The authors conducted a preliminary investigation into the roles of IFNI&III signalling in response to SARS-Cov-2 infection using knock out strains of key signalling components and demonstrated STAT2 signalling played a role in restricting the virus proliferation in the lung and thus disseminating to other tissues but might also be involved in the virus-induced lung injury. Backed by data from viral RNA analysis, transcriptomics, micro-CT, and histopathology, the authors concluded that Syrian hamsters could be developed as the pre-clinical model for vaccine and therapeutic intervention including antiviral and anti inflammatory drug developments in COVID19.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Very limited contribution considering a) high dose of virus used to cause infection and pathology b) no comparable serum markers found in Syrian hamster c) difficult to interpret and connect all the discrete pieces of information on IFN signalling in response to SARS-CoV2.
Understand the virology and/or cell biology of SARS-CoV2/COVID19
Provided evidence on STAT2 in controlling viral replication in the lung.
Others: seem to invite more questions to validate small rodent animal models in Covid-19 and the needs.
· In vivo study: mouse and hamster
Strengths and limitations of the paper
Novelty: Animal model comparisons against human clinical features and diagnosis tools
Standing in the field: Previous studies showed Syrian hamsters to be highly susceptible to SARS-CoV-1 and SARS-CoV-2; their finding about STAT2 is in line with effect of STAT1 in mouse model of SARS- CoV-1 infection but is much in contrast to the generally observation in virus infected Stat2-/- mice and STAT2-/- hamsters. This in itself throws much doubt on rodent animal model development in Covid-19, particularly the genetic differences in immune responses to IFNs.
Appropriate statistics: yes but very small sample size particularly for Figure 2D lung pathologies
Viral model used: an original patient isolate of SARS-CoV-2 (BetaCoV/Belgium/GHB-03021/2020) that was passaged on HuH7 and Vero-E6 cells
Translatability: Hamster to be used a preclinical model is still highly arguable based on the data presented. It is impossible to translate this study in the current format.
a) No prominent pro-inflammatory serum markers similar in covid-19 such as IL6, IL10 and IFNg were found in the hamster model.
b) The high dosage of virus to induce true infection and the short time window in which to follow the infection make the model difficult to recapitulate the different and progressive stages of Covid-19.
c) How STAT2 drives lung tissue damage while still supporting viral replication was not properly discussed. Would a global STAT2 knockout resemble a delayed IFNI response? Also in Stat2-/- mice, Stat seems to lead tissue dependent viral response. This should be an interesting direction to follow.
d) IFNl has been reported to play an essential role in resolving inflammation by restricting the neutrophil infiltration (Udalova group 2015 finding PMID: 25941255). Therefore, the observed increased lung pathology in IL28R-/- could be due to increased neutrophil infiltration into the lung. However, there is evidence from published work (PMID: 32094169) that human neutrophils don’t have IL28R expression. The relevance and translatability of this finding to Covid 19 pathogenesis is questionable.
e) Overall instead of providing solid evidence to support Syrian hamster as a suitable pre-clinical model, this paper exposes more difficulties to correlate findings from this animal model to clinics.