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Association of Neutrophil Gene Expression with 28-Day Ventilator Weaning in COVID-19 ARDS Patients (part 1)

ABSTRACT: Rationale COVID-19 can cause ARDS, a life-threatening condition that requires long-term ventilation. Neutrophil activation is a key mediator of lung injury in ARDS. However, the relationship between peripheral neutrophil RNA expression at the time of severe illness and 28-day ventilator weaning has not yet been clarified. Objectives To clarify the relationship with 28-day ventilator weaning and whole blood RNA sequencing analysis in COVID-19 patients. Moreover, single-cell RNA-seq was performed on neutrophils to analyze changes in gene expression levels for each fraction. Methods Bulk sequencing was performed using whole blood from 28 COVID-19 ARDS patients (9 in the non-ventilator weaning group and 19 in the ventilator weaning group) and 16 healthy controls. Next, single-cell RNA-seq was performed on neutrophils isolated from peripheral blood of 5 COVID-19 ARDS patients (3 in the non-ventilator weaning group and 2 in the ventilator weaning group) and 6 healthy individuals. Measurements and Main Results Although there was no clear difference between the non-ventilator weaning group and the ventilator weaning group in bulk RNA-seq using whole blood, the result of single-cell RNA-seq revealed clear differences between the non-ventilator weaning group, the ventilator weaning group, and healthy individuals. Conclusions Our study suggests that gene expression in neutrophils at the time of severe illness in COVID-19 ARDS patients may be associated with 28-day ventilator weaning.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234902 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS), death and long-term sequelae. Innate immune cells are critical for host defense but are also the primary drivers of ARDS. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial effects of dexamethasone therapy during severe COVID-19 remain speculative, but understanding the mechanistic effects could improve evidence-based therapeutic interventions. To interrogate these relationships, we developed an scRNAseq atlas that is freely accessible (biernaskielab.ca/COVID_neutrophil). We discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. Neutrophils from bacterial ARDS had higher expression of antibacterial molecules such as PLAC8 and CD83. Dexamethasone therapy in COVID patients rapidly altered the IFNactive state, downregulated interferon responsive genes, and activated IL1R2+ve neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1, which were not present in healthy controls. Moreover, dexamethasone remodeled global cellular interactions by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFNactive neutrophils and a greater degree of steroid-induced immature neutrophil expansion. Indeed, the highest proportion of IFNactive neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the molecular benefits of dexamethasone therapy are also defined. The identified molecular pathways can now be targeted to develop improved therapeutics.

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Association of Neutrophil Gene Expression with 28-Day Ventilator Weaning in COVID-19 ARDS Patients (part 1)

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