Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome

Abstract

We analyzed the blood transcriptome of sepsis framed within community-acquired pneumonia (CAP) and characterized its molecular and cellular heterogeneity in terms of functional modules of co-regulated genes with impact for the underlying pathophysiological mechanisms. Our results showed that CAP severity is associated with immune suppression owing to T-cell exhaustion and HLA and chemokine receptor deactivation, endotoxin tolerance, macrophage polarization, and metabolic conversion from oxidative phosphorylation to glycolysis. We also found footprints of host’s response to viruses and bacteria, altered levels of mRNA from erythrocytes and platelets indicating coagulopathy that parallel severity of sepsis and survival. Finally, our data demonstrated chromatin re-modeling associated with extensive transcriptional deregulation of chromatin modifying enzymes, which suggests the extensive changes of DNA methylation with potential impact for marker selection and functional characterization. Based on the molecular footprints identified, we propose a novel stratification of CAP cases into six groups differing in the transcriptomic scores of CAP severity, interferon response, and erythrocyte mRNA expression with impact for prognosis. Our analysis increases the resolution of transcriptomic footprints of CAP and reveals opportunities for selecting sets of transcriptomic markers with impact for translation of omics research in terms of patient stratification schemes and sets of signature genes.

Portrayal of the human blood transcriptome of 3,388 adults and its relation to ageing and health

“…Hence, the spots provide a sort of basis set of co-regulated genes, which further expands into a rich collection of functional annotations of different categories via a multitude of combinations as considered by our cPATs (see above). Correlation analysis of different previous blood signature sets [8,11,52,53] and our spot profiles provides very similar patterns in support of this view on the modular structure of the blood transcriptome ( Figure S Expression of M1 macrophages and dendritic cells associate with the IFN-response signature (spot L).…”

“…Our recent study on sepsis framed by community acquired pneumonia [8], a high-grade inflammatory disease, identified three major axes of the variation of the blood transcriptome, namely the inflammatory axis (endotoxin tolerance, cytotoxic cells), a 'blood-disturbance' axis including mostly erythrocyte and thrombocyte characteristics and the IFN-response axis. These axes of variation were also found in the blood transcriptomes of nominally heathy subjects, however with a decreased amplitude of inflammatory expression changes.…”

“…They were applied in medical context for characterizing diseases such as ischemic stroke [2], Alzheimer's disease [3], epilepsy [4], sepsis [5][6][7][8]; in pharmacogenomics [9] and marker search [10];…”

“…Previously, we have developed an omics 'portrayal' methodology based on self-organizing maps (SOM) machine learning [20,21]. It has been applied to a series of data types and diseases [22][23][24][25][26], among them a study about footprints of pneumonia in the blood transcriptome [8]. SOM-portrayal takes into account the multidimensional nature of gene regulation and pursues a modular view on coexpression, reduces dimensionality and supports visual perception by delivering 'personalized', casespecific transcriptome portraits.…”

Transcription Factors STAT5A and SPI1 Reveals RHBDD2 as a Potential Biomarker in Sepsis and Septic Shock

“…The hub genes of module blue also reported in sepsis and septic shock. ABCE1, RPL15, RPL5, RPS13, RPL31, and RPL7 involved in protein binding and ribosomal functions 35,36 . NCBP2 levels reduced over the passage of sepsis.…”