Abstract
BackgroundDysregulation of the host immune response is a pathognomonic feature of sepsis. Abnormal physiological conditions are understood to shift efficient linear splicing of protein-coding RNA towards non-canonical splicing, characterized by the accumulation of non-coding circularized (circ)RNA. CircRNAs remain unexplored in specific peripheral blood mononuclear cells (PBMCs) during sepsis. We here sought to identify and characterize circRNA expression in specific PBMCs of patients with sepsis due to community-acquired pneumonia (CAP) relative to healthy subjects.MethodsThe study comprised a discovery cohort of six critically ill patients diagnosed with sepsis due to community-acquired pneumonia and four (age, gender matched) healthy subjects. PBMCs were isolated, and fluorescence-activated cell sorting was used to purify CD14+ monocytes, CD4+, CD8+ T cells, and CD19+ B cells for RNA sequencing. CD14+ monocytes from independent six healthy volunteers were purified, and total RNA was treated with or without RNase R.ResultsRNA sequencing of sorted CD14+ monocytes, CD4+, CD8+ T cells, and CD19+ B cells from CAP patients and healthy subjects identified various circRNAs with predominantly cell-specific expression patterns. CircRNAs were expressed to a larger extent in monocytes than in CD4+, CD8+ T cells, or B cells. Cells from CAP patients produced significantly higher levels of circRNA as compared to healthy subjects. Considering adjusted p values, circVCAN (chr5:83519349-83522309) and circCHD2 (chr15:93000512-93014909) levels in monocytes were significantly altered in sepsis. Functional inference per cell-type uncovered pathways mainly attuned to cell proliferation and cytokine production. In addition, our data does not support a role for these circRNAs in microRNA sequestration. Quantitative PCR analysis in purified monocytes from an independent group of healthy volunteers confirmed the existence of circVCAN and circCHD2.ConclusionsWe provide a benchmark map of circRNA expression dynamics in specific immune cell subsets of sepsis patients secondary to CAP. CircRNAs were more abundant in immune cells of sepsis patients relative to healthy subjects. Further studies evaluating circRNA expression in larger cohorts of sepsis patients are warranted.
Highlights
Dysregulation of the host immune response is a pathognomonic feature of sepsis
We provide a benchmark map of Circular RNA (circRNA) expression dynamics in specific immune cell subsets of sepsis patients secondary to community-acquired pneumonia (CAP)
CircRNAs were more abundant in immune cells of sepsis patients relative to healthy subjects
Summary
Dysregulation of the host immune response is a pathognomonic feature of sepsis. We here sought to identify and characterize circRNA expression in specific PBMCs of patients with sepsis due to community-acquired pneumonia (CAP) relative to healthy subjects. Sepsis is a complex syndrome initiated by an imbalanced reaction to infection, with community-acquired pneumonia (CAP) as a major cause, leading to organ damage and high mortality rates [1, 2]. The immunopathology of sepsis is understood to encompass a plethora of host defense reactions that are primarily categorized as either abnormally excessive or suppressed [4]. Prospective observational cohorts to study the genomics of sepsis have shown that patients present signatures of both sustained inflammation and immune suppression [6,7,8]. Identifying regulatory features of the genomic response in sepsis is crucial for future drug discovery
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