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Serial whole blood transcriptomic analysis demonstrates activation of neutrophils, platelets and coagulation in severe and critical COVID-19 – submitted

ABSTRACT: Introduction: A maladaptive inflammatory response has been implicated in the pathogenesis of severe and critical COVID-19. This study aimed to characterize the temporal dynamics of this response and investigate whether critical disease is associated with distinct gene expression patterns. Methods: We performed microarray analysis of serial whole blood RNA samples from 19 patients with critical COVID-19, 15 patients with severe but non-critical disease and 11 healthy controls. We assessed whole blood gene expression patterns by differential gene expression analysis, gene set enrichment, two clustering methods and estimated relative leukocyte abundance using CIBERSORT. Results: Neutrophils, platelets, cytokine signaling, and the coagulation system were activated in COVID-19, and more pronounced in critical vs. non-critical disease. We observed two different trajectories of neutrophil-associated genes, indicating the emergence of a more immature neutrophil phenotype over time. Interferon-associated genes were strongly enriched in early COVID-19 before falling markedly, with modest severity-associated differences in trajectory. Conclusions: Severe COVID-19 is associated with a broad inflammatory response, which is more pronounced in critical disease. Our data suggest a progressively more immature circulating neutrophil phenotype over time. Interferon signaling is enriched in COVID-19 but does not seem to drive critical disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213313 | GEO | 2023/02/13

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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Serial whole blood transcriptomic analysis demonstrates activation of neutrophils, platelets and coagulation in severe and critical COVID-19 – submitted

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