Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Blood transcriptome of human bacterial and influenza A pneumonia

ABSTRACT: Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly. Daily PAXgene samples for up to 5 days for; influenza A pneumonia patients (n=8), bacterial pneumonia patients (n=16), mixed bacterial and influenza A pneumonia patients (n=3), systemic inflammatory response patients (SIRS, n=13). Days 1 and 5 PAXgene samples for healthy control individuals

ORGANISM(S): Homo sapiens

SUBMITTER: Grant Parnell

PROVIDER: E-GEOD-40012 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Critical disease caused by the new 2009 pandemic influenza virus (nvH1N1) is a challenge for physicians and scientist. As evidenced in SARS and H5N1, the development of an effective immune response plays a key role to overcome viral diseases. We studied host`s gene expression signatures, cytokine and antibody responses along the first week of hospitalization in 19 critically ill patients with primary nvH1N1 pneumonia and two degrees of respiratory involvement. Presence of comorbidities and absence of immunosuppresory conditions were the common antecedents in both groups. The most severe patients (n=12) showed persistant respiratory viral secretion, increased levels of pro-inflammatory cytokines and chemokines in serum, and elevated systemic levels of two immunosuppresory cytokines (IL-10 and IL-1ra). Both groups were able to produce specific antibodies against the virus. The average day for antibody production was day 9 in the course of the disease, defining an early period of innate immunity and a late period of adaptive immunity. The most severe group evidenced a poor expression of a set of MHC class II and T cell receptor (TCR) related genes participating in antigen presentation and cell mediated immune responses in the late phase. 7 patients of this group finally died. This findings evidence that, as observed in sepsis, severe H1N1 disease course with immunoparalysis, which could explain the poor control of the virus along with the increased incidence of bacterial superinfection observed in these patients. 19 patients attending to the participants ICUs with primary viral pneumonia during the acute phase of influenza virus illness with acute respiratory distress and unequivocal alveolar opacification involving two or more lobes with negative respiratory and blood bacterial cultures at admission were recruited from November the 1st to December the 31st 2009. Serial blood samples for plasma, serum and RNA were collected by using Serum, EDTA and PaxGene (BD®) venous blood vacuum collection following manufacturer instructions at day 1, 3/5 and 7 according to an unified protocol for all the participant ICUs. A pharyngeal sample was collected in paralel. RNA from blood was processed for gene expression analysis by using Sentrix Human-6 v2 Expression BeadChips (Illumina, San Diego, CA). RNA from blood obtained from 4 healthy controls was used for comparison purposes. Samples were distributed in four groups depending on whether or not the patients nedeed of mechanical ventilation, and on the early/late phase of the disease (before or after day 9 respectively).

Project description:Diagnosis of acute infection in the critically ill remains a challenge. Changes in physiologic parameters and existing molecular diagnostics are not specific and microbiologic confirmation of infection can take days. As cellular first responders, preclinical studies indicate that circulating leukocytes are activated in response to bacterial infection, manifesting infection-specific transcriptional programs. We hypothesized that circulating leukocyte transcriptional profiles can be used to diagnose infection and monitor response to therapy in the critically ill. Experiment Overall Design: A translational research approach was employed. Fifteen mice underwent intratracheal (i.t.) injections of live P. aeruginosa, P. aeruginosa endotoxin, live S. pneumoniae, or normal saline. At 24 hours after injury, GeneChip microarray analysis of circulating buffy coat RNA identified 219 genes that distinguished between the pulmonary insults and differences in 7-day mortality. Similarly, buffy coat microarray expression profiles were generated from 20 mechanically ventilated patients every two days for up to three weeks; 11 of these patients developed pneumonia. Principal components analysis of the expression levels of the human orthologs for the mouse genes resulted in gene expression trajectories that describe the cohort of 11 patients as they develop, are treated for, and convalesce from ventilator-associated pneumonia (VAP). When the VAP microarray profiles were analyzed independently, 85 genes were identified with consistent changes in abundance during the seven days bracketing the diagnosis of VAP. The estimated prediction accuracy in this small patient cohort was 91%. The abundance of select transcripts was validated using real-time PCR. Principal components analysis of the average microarray-measured abundances of these genes defined a general trajectory (riboleukogram) for the onset of acute infection in this patient population. Individual riboleukograms demonstrated that the onset and course of infection are specific for each individual, but as patients recover from infection the riboleukograms converge. The gene ontologies of the co-expression networks indicate that leukocyte chemokines and granule maturation are especially informative for pneumonia diagnostics.

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Blood transcriptome of human bacterial and influenza A pneumonia

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