Project description:Background: Community-acquired pneumonia (CAP) is defined as an acute lung infection involving the alveoli that occurs in a patient without recent health care exposure. A complication of CAP is severe sepsis, a syndrome of infection often accompanied by systemic inflammation and organ dysfunction. The aim of this study was to evaluate mRNA and miRNA in whole blood and to perform an integrative analysis to assess cellular signals that play a role in the pathogenesis of patients with CAP-associated sepsis. Methods: This was a prospective, observational, single-center study of patients transported to the Department of Traumatology and Acute Critical Medicine, Graduate School of Medicine, Osaka University. Patients with CAP-associated sepsis were analyzed. The diagnosis of pneumonia was made according to the clinical findings, including blood samples and chest computed tomography scan, and the diagnosis of sepsis followed the Sepsis-3 guidelines. Results: We included 14 critically ill patients with CAP-associated sepsis and 15 healthy control subjects (HCS). The median ages of the patient group and HCS were 78 and 55 years, and their body mass indexes were 22.8 and 21.7 kg/m2, respectively. All patients were treated at the critical care center, and 11 of the 14 patients received ventilatory management. All patients survived. These 14 patients met the diagnostic criteria of Sepsis-3 and were diagnosed as having CAP-associated sepsis. Of them, 6 patients met the diagnostic criteria for septic shock. RNA sequencing showed the number of genes with up:down (upregulated:downregulated) expression variation (false discovery rate [FDR] <0.05, |log2 fold change| >1.2) to be 1209:1461 for mRNA; 51:21 for microRNA; and 646:1274 for miRNA-targeted mRNA. Canonical pathway analysis using mRNA showed activation of the PD-1 and PD-L1 cancer immunotherapy signaling pathways and inhibition of the Th1 signaling pathway as well as that using miRNA-targeted mRNAs. Conclusions: Using integrated analysis of mRNA and miRNA, we elucidated for the first time, to our knowledge, that T-cell exhaustion occurred during the acute phase of CAP-associated sepsis and that miRNA regulated Th1 signaling and PD-1 and PD-L1 cancer immunotherapy signaling through the RNA interference action of mRNA.

Project description:Sepsis is defined as a systemic inflammatory response secondary to a proven or suspected infection. Mechanisms governing this inflammatory response have been shown to be complex and dynamic, involving cross-talking among diverse signaling pathways. However, current knowledge on mechanisms underlying sepsis is far from providing a complete picture of the syndrome, justifying additional efforts that might add to this scenario. Microarray-based expression profiling is a powerful approach for the investigation of complex clinical conditions such as sepsis: the analysis of gene transcription at the genome level potentially avoids results derived from biased assumptions. In this study we investigate whole-genome gene expression profiles of mononuclear cells from survivor and non-survivor septic patients. Blood samples were collected at the time of sepsis diagnosis and seven days later, allowing us to evaluate the role of biological processes or genes possibly involved in patient recovery. Aiming to circumvent, at least partially, the heterogeneity of septic patients we included only patients admitted with sepsis caused by community-acquired pneumonia. Global gene expression profiling allowed us to characterize early sepsis, as compared to healthy individuals. Our results corroborate literature reports on inflammation response in the early stages of sepsis but highlight great heterogeneity in gene expression during sepsis progress. Additionally, global gene expression in the early stage was also able to distinguish sepsis from septic shock and correlated with patient outcome. Differences in oxidative stress seem to be associated with clinical outcome, since significant differences in the expression profile of related genes were observed between survivors and non-survivors at the time of patient enrollment (early sepsis). However, our results substantiate current knowledge supporting that sepsis syndrome development is indeed multifaceted. Although the initial infection of enrolled patients was pneumonia, seven days later gene expression profiles seemed to be characteristic of each patient, common gene expression changes distinguishing survivors from non-survivors. This result could be associated with the underlying health status of each one of them, with complications due to sepsis itself as well as with distinct timing for response to treatment. In this study we investigate whole-genome gene expression profiles of mononuclear cells from survivor (n=5) and non-survivor (n=5) septic patients, as well as from 3 healthy controls. Blood samples were collected at the time of sepsis diagnosis and seven days later, allowing us to evaluate the role of biological processes or genes possibly involved in patient recovery. Aiming to circumvent, at least partially, the heterogeneity of septic patients we included only patients admitted with sepsis caused by community-acquired pneumonia.

			Action	DRS
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	SRR24015307.fastq.gz	Fastqsanger.gz
	SRR24015308.fastq.gz	Fastqsanger.gz
	SRR24015309.fastq.gz	Fastqsanger.gz
	SRR24015310.fastq.gz	Fastqsanger.gz

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Integrated analysis of messenger RNA and microRNA in patients with community-acquired pneumonia associated sepsis (miRNA part)

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