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Review 1: "Targeting Neutrophils Extracellular Traps (NETs) Reduces Multiple Organ Injury in a COVID-19 Mouse Model"

Both reviewers agree that this study may have important implications for DNase as a therapeutic agent for COVID-19. Reviewers point out the small sample size and short follow-up period as potential limitations.

Published onJul 19, 2022
Review 1: "Targeting Neutrophils Extracellular Traps (NETs) Reduces Multiple Organ Injury in a COVID-19 Mouse Model"
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Targeting Neutrophils Extracellular Traps (NETs) reduces multiple organ injury in a COVID-19 mouse model
Description

ABSTRACTCOVID-19 is characterized by severe acute lung injury, which is associated with neutrophils infiltration and release of neutrophil extracellular traps (NETs). COVID-19 treatment options are scarce. Previous work has shown an increase in NETs release in the lung and plasma of COVID-19 patients suggesting that drugs that prevent NETs formation or release could be potential therapeutic approaches for COVID-19 treatment. Here, we report the efficacy of NET-degrading DNase I treatment in a murine model of COVID-19. DNase I decreased detectable levels of NETs, improved clinical disease, and reduced lung, heart, and kidney injuries in SARS-CoV-2-infected K18-hACE2 mice. Furthermore, our findings indicate a potential deleterious role for NETs lung tissue in vivo and lung epithelial (A549) cells in vitro, which might explain part of the pathophysiology of severe COVID-19. This deleterious effect was diminished by the treatment with DNase I. Together, our results support the role of NETs in COVID-19 immunopathology and highlight NETs disruption pharmacological approaches as a potential strategy to ameliorate COVID-19 clinical outcomes.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

The manuscript by Veras et al have provided an important clue that targeting NETosis/NETs formation alleviates acute lung pathology and damage of other organs in SARS-COV-2 infection using K18-hACE2 murine animal model. The results from this study show positive outcome of DNAse-1 therapy and describe reduced clinical signature and multi-organ-injury. This study used DNAse-1 treatment before infection, indicating the use of a prophylactic administration of DNAse-1 in mitigate NETs-induced organ damage in SARS-COV-2 infection. 

However, one of the major limitations of this study is that the protective effects of DNASe-1 was monitored only up to 5 days post infection, while in a majority of clinical observations, hospitalized patients develop multi-organ failure and progressive lung damage in ICU between 2-4 weeks. The long-term impact of DNAse-1 treatment was not addressed nor discussed. 

Although, this study highlights the importance in degrading extracellular chromatin DNA in NETs, it is not clear the fate of degraded NETs by-products that are released in the lung micro-environment. As, many studies implicated NETs protein components (histones ex. histone H2A, H3 or H4) in acute lung injury and multi-organ failure. The authors have not discussed these issues. 

It is not clear whether DNAse-1 treatment effects the viral loads. Association of DNAse with virus replication/spread was not addressed. Also, it is unclear whether the damage in other organs such as heart and liver are mediated by NETs alone of viral-inflicted cytopathic effect in this murine model.

Although NETs were shown significantly decreased, the DNASe-1 treatment has shown little impact on neutrophil influx, which was not clearly represented in histopathology image. 



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