A network-based analysis of systemic inflammation in humans

Abstract

Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

Clinical review: Sepsis and septic shock - the potential of gene arrays

“…The level of significance is directly proportional to the number of genes in the list that correspond to the given biological function, and indirectly proportional to the total number of genes in the list. A related approach to assigning biological meaning to gene lists involves the generation of gene networks based on known, direct and indirect, interactions between genes [16,17]. …”

“…More recently, the genome-level response during experimental human endotoxemia has been studied using microarray technology [16,22,23]. Talwar and colleagues [22] compared eight volunteers challenged with intravenous endotoxin to four controls challenged with saline.…”

“…Calvano and colleagues [16] also studied normal volunteers subjected to a single endotoxin challenge, but applied a (then) novel approach to microarray data analysis centered on knowledge-based interactive gene networks. Again, the maximal up-regulation of gene networks corresponding to inflammation and innate immunity occurred at approximately 6 hours after the endotoxin challenge, and generally returned to baseline by 24 hours.…”

A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis

“…Nevertheless, network-based analyses have recently been described in DNA microarray studies of human disease. 11,14 The latter report, published in Nature, describes a bioinformatic program that was used to organize all differentially expressed genes into a gene interaction network. 14 This program was based on the manual review of over 200 000 scientific publications.…”

Complexity Science to Conceptualize Health and Disease: Is It Relevant to Clinical Medicine?

“…18 These patterns of expressed surface proteins are in turn determined mostly by networks of genes that are differentially activated during infections and sepsis. 19 The interrelated and dynamic response by the host during septic shock could be well described from the viewpoint of CS. Septic shock could then be viewed as an emergent property of a CAS (in this instance, the human body) in which a complex interplay of nonlinear interactions with feedback loops has occurred in a number of subsystems with fuzzy borders.…”