Using systems biology to simplify complex disease: Immune cartography

Abstract

What if there was a rapid, inexpensive, and accurate blood diagnostic that could determine which patients were infected, identify the organism(s) responsible, and identify patients who were not responding to therapy? We hypothesized that systems analysis of the transcriptional activity of circulating immune effector cells could be used to identify conserved elements in the host response to systemic inflammation, and furthermore, to discriminate between sterile and infectious etiologies. We review herein a validated, systems biology approach demonstrating that 1) abdominal and pulmonary sepsis diagnoses can be made in mouse models using microarray (RNA) data from circulating blood, 2) blood microarray data can be used to differentiate between the host response to Gram-negative and Gram-positive pneumonia, 3) the endotoxin response of normal human volunteers can be mapped at the level of gene expression, and 4) a similar strategy can be used in the critically ill to follow septic patients and quantitatively determine immune recovery. These findings provide the foundation of immune cartography and demonstrate the potential of this approach for rapidly diagnosing sepsis and identifying pathogens. Further, our data suggest a new approach to determine how specific pathogens perturb the physiology of circulating leukocytes in a cell-specific manner. Large, prospective clinical trails are needed to validate the clinical utility of leukocyte RNA diagnostics (e.g., the riboleukogram).

Gene expression profiling in sepsis: timing, tissue, and translational considerations

“…Approaches include Markov models [66–68], analyses of variance [69], and the use of cubic splines to model changing expression levels over time [70]. Time course gene expression data from trauma and burn patients have been used to develop statistical methods for the analysis of leukocyte gene expression over time, such as the riboleukogram, which uses principal components analysis to graphically represent a patient’s genomic trajectory over time [36,71]. Results from these studies suggest that genomic profiles in sepsis oscillate around a baseline immune attractor state.…”

“…Results from these studies suggest that genomic profiles in sepsis oscillate around a baseline immune attractor state. Early results support an increased between-patient variance in gene expression at the height of the acute inflammatory phase, with differences between individuals diminishing as patients return to a baseline state of health [71]. As these statistical and computational methods evolve, comparison of gene expression trajectories in sepsis may provide even greater insight into the molecular physiology of sepsis than comparison of gene expression at a single time point.…”

Detection and Quantification of Cytokines and Other Biomarkers

“…The cytokine profile as a whole and the relative abundance of one cytokine, and the endogenous inhibitors, define an inflammatory process that is in motion (2). Cytokines may be used to describe the nature of the insult, infection, or injury (3), and may even be used to stage the disease process (4). These studies revolve around the ability to detect, quantify, and discriminate a single cytokine from a multitude of biomolecules present in any given sample.…”

Hematopoiesis and its disorders: a systems biology approach

“…Inflammation induced by infectious agents involves a network of cytokines, released locally and systemically. 59,60 Neutrophils and macrophages provide a frontline of host defense, quickly recruited by soluble mediators released by both host and foreign agents (such as bacterial lipopolysaccharides). The bone marrow must also respond rapidly by increasing neutrophil production and their exit.…”