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Using RNA-Seq to Investigate Immune-Metabolism Features in Immunocompromised Patients With Sepsis.

ABSTRACT: Objective: Sepsis is life threatening and leads to complex inflammation in patients with immunocompromised conditions, such as cancer, and receiving immunosuppressants for autoimmune diseases and organ transplant recipients. Increasing evidence has shown that RNA-Sequencing (RNA-Seq) can be used to define subendotype in patients with sepsis; therefore, we aim to use RNA-Seq to identify transcriptomic features among immunocompromised patients with sepsis. Methods: We enrolled patients who were admitted to medical intensive care units (ICUs) for sepsis at a tertiary referral centre in central Taiwan. Whole blood on day-1 and day-8 was obtained for RNA-Seq. We used Gene Set Enrichment Analysis (GSEA) to identify the enriched pathway of day-8/day-1 differentially expressed genes and MiXCR to determine the diversity of T cell repertoire. Results: A total of 18 immunocompromised subjects with sepsis and 18 sequential organ failure assessment (SOFA) score-matched immunocompetent control subjects were enrolled. The ventilator-day, ICU-stay, and hospital-day were similar between the two groups, whereas the hospital mortality was higher in immunocompromised patients than those in immunocompetent patients (50.0 vs. 5.6%, p < 0.01). We found that the top day-8/day-1 upregulated genes in the immunocompetent group were mainly innate immunity and inflammation relevant genes, namely, PRSS33, HDC, ALOX15, FCER1A, and OLR1, whereas a blunted day-8/day-1 dynamic transcriptome was found among immunocompromised patients with septic. Functional pathway analyses of day-8/day-1 differentially expressed genes identified the upregulated functional biogenesis and T cell-associated pathways in immunocompetent patients recovered from sepsis, whereas merely downregulated metabolism-associated pathways were found in immunocompromised patients with septic. Moreover, we used MiXCR to identify a higher diversity of T cell receptor (TCR) in immunocompetent patients both on day-1 and on day-8 than those in immunocompromised patients. Conclusions: Using RNA-Seq, we found compromised T cell function, altered metabolic signalling, and decreased T cell diversity among immunocompromised patients with septic, and more mechanistic studies are warranted to elucidate the underlying mechanism.

SUBMITTER: Cheng PL

PROVIDER: S-EPMC8718501 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSepsis is a life-threatening organ dysfunction syndrome that leads to the massive death of immune cells. Long non-coding RNAs (lncRNAs) have been reported to exert key regulatory roles in cells. However, it is unclear how lncRNAs regulate the survival of immune cells in the occurrence and development of sepsis.MethodsIn this study, we used blood whole transcriptome sequencing data (RNA-seq) from normal controls (Hlty) and patients with uncomplicated infection (Inf1 P), sepsis (Seps P), and septic shock (Shock P), to investigate the fraction changes of immune cell types, expression pattern of cell death-related genes, as well as differentially expressed lncRNAs. Association network among these factors was constructed to screen out essential immune cell types, lncRNAs and their potential targets. Finally, the expression of lncRNAs and cell death genes in sepsis patients were validated by qRT-PCR.ResultsIn this study, we found fifteen immune cell types showed significant fraction difference between Hlty and three patient groups. The expression pattern of cell death-related genes was also dysregulated in Hlty compared with patient groups. Co-expression network analysis identified a key turquoise module that was associated with the fraction changes of immune cells. We then identified differentially expressed lncRNAs and their potential targets that were tightly associated with the immune cell dysregulation in sepsis. Seven lncRNAs, including LINC00861, LINC01278, RARA-AS1, RP11-156P1.3, RP11-264B17.3, RP11-284N8.3 and XLOC_011309, as well as their co-expressed cell death genes, were finally identified, and we validated two lncRNAs (LINC00861 and LINC01278) and four mRNA targets using qRT-PCR in sepsis samples.ConclusionThe global analysis of cell death-related genes in the occurrence and development of sepsis was carried out for the first time, and its expression regulation mode was displayed. The expression pattern of sepsis-associated lncRNAs were analyzed and identified, and the lncRNAs were significantly related to the change of immune cell proportion. We highlight the important roles of lncRNAs and their potential targets in the regulation of immune cell fraction changes during sepsis progression. The identified lncRNAs and their target genes may become new biomarkers and therapeutic targets of sepsis.

Project description:BackgroundCircular RNA (circRNA) is one type of noncoding RNA that forms a covalently closed continuous loop. Similar to long noncoding RNA (lncRNA), circRNA can act as microRNA (miRNA) 'sponges' to regulate gene expression, and its abnormal expression is related to diseases such as atherosclerosis, nervous system disorders and cancer. So far, there have been no systematic studies on circRNA abundance and expression profiles in human adult and fetal tissues.ResultsWe explored circRNA expression profiles using RNA-seq data for six adult and fetal normal tissues (colon, heart, kidney, liver, lung, and stomach) and four gland normal tissues (adrenal gland, mammary gland, pancreas, and thyroid gland). A total of 8120, 25,933 and 14,433 circRNAs were detected by at least two supporting junction reads in adult, fetal and gland tissues, respectively. Among them, 3092, 14,241 and 6879 circRNAs were novel when compared to the published results. In each adult tissue type, we found at least 1000 circRNAs, among which 36.97-50.04% were tissue-specific. We reported 33 circRNAs that were ubiquitously expressed in all the adult tissues we examined. To further explore the potential "housekeeping" function of these circRNAs, we constructed a circRNA-miRNA-mRNA regulatory network containing 17 circRNAs, 22 miRNAs and 90 mRNAs. Furthermore, we found that both the abundance and the relative expression level of circRNAs were higher in fetal tissue than adult tissue. The number of circRNAs in gland tissues, especially in mammary gland (9665 circRNA candidates), was higher than that of other adult tissues (1160-3777).ConclusionsWe systematically investigated circRNA expression in a variety of human adult and fetal tissues. Our observation of different expression level of circRNAs in adult and fetal tissues suggested that circRNAs might play their role in a tissue-specific and development-specific fashion. Analysis of circRNA-miRNA-mRNA network provided potential targets of circRNAs. High expression level of circRNAs in mammary gland might be attributed to the rich innervation.

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Using RNA-Seq to Investigate Immune-Metabolism Features in Immunocompromised Patients With Sepsis.

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