Extracellular ISG15 drives severe respiratory pathology during viral infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA623911 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11511066.fastq.gz | Fastqsanger.gz | |||
| SRR11511067.fastq.gz | Fastqsanger.gz | |||
| SRR11511068.fastq.gz | Fastqsanger.gz | |||
| SRR11511069.fastq.gz | Fastqsanger.gz | |||
| SRR11511070.fastq.gz | Fastqsanger.gz |
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Project description:Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production and signaling have been reported to be causal in cytokine storm associated pathology in several respiratory viral infections, however, the mechanisms by which IFN-I promotes disease pathogenesis remain poorly understood. We report using Usp18-deficient, USP18 enzymatic inactive and Isg15-deficient mouse models that lack of deISGylation during persistent viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. Transcriptional studies of immune cells from mice bearing the enzymatic inactive version of USP18 (Usp18C61A) revealed a neutrophil influx in the lung of these animals during infection, associated with increased immature neutrophil content. These neutrophil differentiation changes were dependent on ISG15 as deletion of Isg15 from C61A animals reversed the accumulation of immature neutrophils. Importantly, neutrophil depletion reversed morbidity and mortality in Usp18C61A mice. In summary, we reveal Usp18 enzymatic function is crucial for regulating extracellular release of ISG15 which are accompanied by altered neutrophil differentiation, cytokine amplification and mortality following persistent viral infection.
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Project description:Various lung insults can result in replacement of resident alveolar macrophages (AM) by blood monocyte-derived (BMo)-AM. However, the dynamics of this process and its long-term consequences for respiratory viral infections remain unclear. Using several mouse models and a marker to unambiguously track fetal monocyte-derived (FeMo)-AM and BMo-AM, we established the kinetics and extent of replenishment and their function to recurrent influenza virus (IAV) infection. Massive loss of FeMo-AM resulted in rapid replenishment by self-renewal of survivors followed by generation of BMo-AM, which progressively outcompeted FeMo-AM over several months due to increased glycolytic and proliferative capacity. The presence of both naïve and experienced BMo-AM conferred severe pathology to IAV infection, which was associated with a pro-inflammatory phenotype. Furthermore, upon aging of naïve mice, FeMo-AM are gradually replaced by BMo-AM, which contribute to IAV disease severity in a cell autonomous manner. Taken together, our results suggest that origin rather than training of AM determines long-term function to respiratory viral infection and provide an explanation for increased severity in elderly.
2022-07-01 | GSE202001 | GEO
Project description:Various lung insults can result in replacement of resident alveolar macrophages (AM) by blood monocyte-derived (BMo)-AM. However, the dynamics of this process and its long-term consequences for respiratory viral infections remain unclear. Using several mouse models and a marker to unambiguously track fetal monocyte-derived (FeMo)-AM and BMo-AM, we established the kinetics and extent of replenishment and their function to recurrent influenza virus (IAV) infection. Massive loss of FeMo-AM resulted in rapid replenishment by self-renewal of survivors followed by generation of BMo-AM, which progressively outcompeted FeMo-AM over several months due to increased glycolytic and proliferative capacity. The presence of both naïve and experienced BMo-AM conferred severe pathology to IAV infection, which was associated with a pro-inflammatory phenotype. Furthermore, upon aging of naïve mice, FeMo-AM are gradually replaced by BMo-AM, which contribute to IAV disease severity in a cell autonomous manner. Taken together, our results suggest that origin rather than training of AM determines long-term function to respiratory viral infection and provide an explanation for increased severity in elderly.
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Project description:Type I interferons (IFN-I) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of thousands of IFN-I stimulated genes (ISGs), whose aggregate function results in the control of viral infections. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, often self-resolving, mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance. Inspired by the antiviral state of humans with ISG15 deficiency, we identified a nominal collection of 10 ISGs that recapitulated the broad antiviral potential of the IFN-I system, which typically induces the expression of thousands of ISGs. The expression of this 10-ISG collection in an IFN-I non-responsive cell line increased cellular resistance to Zika virus, vesicular stomatitis virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A lipid nanoparticle-encapsulated mRNA formulation of this 10-ISG collection significantly reduced IAV plaque size in vivo in mice when given prophylactically. Moreover, when used collectively and delivered prophylactically, 10-ISG was able to protect hamsters against a lethal SARS-CoV-2 challenge, in contrast with the lack of efficacy when mRNAs were delivered individually. These findings suggest that these 10 ISGs have potential as a broad-spectrum antiviral prophylactic.
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