Systems Biology of Staphylococcus Aureus Infection Ex Vivo and in Vitro

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Title: Systems Biology of Staphylococcus Aureus Infection Ex Vivo and in Vitro
Author: Banchereau, Romain
Abstract: Staphylococcus aureus has emerged as one of the most common community -acquired bacterial infections , with significant morbidity and mortality . Emergence of multidrug resistant strains worldwide , combined with limited treatment options demand novel approaches to further elucidate host -pathogen interactions , and especially host responses to infection . To this end , we leveraged systems biology approaches to better characterize the status of the host immune system during S . aureus infection ex vivo and in vitro . The transcriptional profiles of PBMC and whole blood from patients with community -acquired S . aureus infection were characterized by microarray analysis , and leukocyte population frequencies were measured by polychromatic flow cytometry . To refine our understanding of inflammatory networks involved , an in vitro system of antigen -presenting cell stimulation with various pathogens , including S . aureus as well as other bacteria and viruses , and their components , was used to identify early inflammatory programs induced in innate immune cells . To reduce the dimension and complexity of the data generated , we developed modular frameworks to analyze and interpret the fingerprints obtained from both the ex vivo and in vitro studies . / / Overall , the blood transcriptional response to S . aureus infection was characterized by over -expression of innate immunity and hematopoiesis transcriptional programs , and under -expression of adaptive immunity programs . Flow cytometry and standard cell blood count (CBC ) revealed an increase in absolute numbers of circulating monocytes , neutrophils and antigen -presenting cells , including dendritic cells and B cells , combined with a decrease in central memory T cells . To identify transcriptional correlates of clinical heterogeneity , we obtained individual fingerprints and derived the molecular distance to health , a numerical score of transcriptional perturbation for each patient . Patient -by -patient analysis without a priori knowledge of clinical diagnoses identified four major transcriptional clusters based on inflammation , erythropoiesis and interferon -induced profiles . Clinical presentation , bacterial dissemination and time between hospitalization and blood sampling were identified as major factors influencing the signature . The framework obtained from in vitro stimulation of monocyte -derived DC helped us refine the characterization of inflammatory programs activated during S . aureus infection . In addition to inflammatory antibacterial programs , S . aureus induced a subset of interferon response modules , also observed in viral infections and autoimmunity , as well as a specific set of modules linked to cell compartmentalization and lipid biosynthesis . Systems biology approaches provide a global and comprehensive assessment of host responses to acute bacterial infections , bringing a new understanding of disease pathogenesis and underlying patient heterogeneity . [Keywords ; Staphylococus aureus , microarray , systems biology , module framework , transcription]
URI: http : / /hdl .handle .net /2152 .5 /983
Date: 2012-07-09


Systems Biology of Staphylococcus Aureus Infection Ex Vivo and in Vitro. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /983 .

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