Unknown,Transcriptomics,Genomics,Proteomics

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Post-natal age is a critical determinant of the neonatal host response to sepsis

ABSTRACT: Neonates manifest a unique host response to sepsis even among other children. Preterm neonates may experience sepsis soon after birth or during often protracted birth hospitalizations as they attain physiologic maturity. We examined the transcriptome using genome-wide expression profiling on prospectively collected peripheral blood samples from infants evaluated for sepsis within 24 hours after clinical presentation. Simultaneous plasma samples were examined for alterations in inflammatory mediators. Group designation (sepsis or uninfected) was determined retrospectively based on clinical exam and laboratory results over the next 72 hours from the time of evaluation. Unsupervised analysis showed the major node of separation between groups was timing of sepsis episode relative to birth (early, <3 days or late, >3 days). Principal component analyses revealed significant differences between patients with early or late sepsis despite the presence of similar key immunologic pathway aberrations in both groups. Unique to neonates, the uninfected state and host response to sepsis is significantly affected by timing relative to birth. Future therapeutic approaches may need to be tailored to the timing of the infectious event based on post-natal age. We used human microarrays to detail the molecular profile of the events that occur following sepsis in hospitalized neonates Please note that 'uninfected chorio' represents babies who were not infected but had chorioamnionitis exposure

ORGANISM(S): Homo sapiens

SUBMITTER: M Cecilia Lopez

PROVIDER: E-GEOD-69686 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Melioidosis, caused by Gram negative bacteria Burkholderia pseudomallei, is a major type of community-acquired septicemia in Southeast Asia and Northern Australia with high mortality and morbidity rate. More accurate and rapid diagnosis is needed for improving the management of septicemic melioidosis. We previously identified 37-gene candidate signature to distinguish septicemic melioidosis from sepsis due to other pathogens. The aims of this current study were to independently validate our previous biomarker and consolidate gene selection from each of our microarray data set for establishing a targeted assay for the differential diagnosis of melioidosis. Blood samples were collected from patients who presented with severe inflammatory response syndromes from 3 provincial hospitals in Northeast of Thailand during September 2009 and November 2011. Only culture-confirmed sepsis were included in the study (n=166). We generated a new microarray dataset comprising of 29 patients with septicemic melioidosis and 54 patients with sepsis due to other pathogens. Validation of the 37-gene signature using this new dataset demonstrated the prediction accuracy of approximately 80% for detecting type of sepsis. In order to develop a nanoliter-scale high throughput PCR technology, we further identified additional gene signature from this new microarray dataset and by revisiting our published data. Altogether 85 genes including 6 housekeeping genes were selected. Using multi-steps iteration approach we could reduce the number of biomarkers to 12 genes while the performance is comparable to that of the full panel. The high performance (accuracy >70%) of this 12-gene signature could be validated in a second independent set of samples. The 12-gene panel identified by our study provides high performance for the differential diagnosis of septicemic melioidosis. This finding will be useful for improving the management of septicemic melioidosis in term of diagnosis, treatment and follow up. Total RNA from whole blood obtained from patients with sepsis caused by B.pseudomallei (n=29) or other pathogens (n=54) and uninfected controls (28 healthy and 27 subjects with type 2 diabetes mellitus) were collected. In order to validate the published signature, microarray data were generated from these samples. This dataset was also used for an independent selection of signature for septicemic melioidosis. The same RNA samples were used for validation by a high throughput real-time PCR technique, Fluidigm.

Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. For the RNA-Seq study reported here, 73 patients were recruited with deferred consent at the time of first examination in an emergency ward based on the opinion of physicians that there was a potential for the patient's condition to develop into sepsis. These were retrospectively divided into groups based on clinical features and compared to 11 non-urgent surgical controls.

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Post-natal age is a critical determinant of the neonatal host response to sepsis

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