A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.human disease | translational medicine | inflammation | immune response | injury M urine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials (1-3). However, few of these human trials have shown success (4-7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed (8-11). Despite commentaries that question the merit of an overreliance of animal systems to model human immunology (3,12,13), in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14-18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16-18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models.In this article, we report on a systematic comparison of the genomic respo...

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

The hrp genes of Pseudomonas syringae pv. phaseolicola control the development of primary disease symptoms in bean plants and the elicitation of the hypersensitive response in resistant plants. We examined the expression of the seven operons located in the 22-kb hrp cluster (L. G. Rahme, M. N. Mindrinos, and N. J. Panopoulos, J. Bacteriol. 173:575-586, 1991) A set of genes called hrp ("harp") (27) controls the ability of phytopathogenic bacteria to cause disease on susceptible plants and to elicit the hypersensitive response on resistant plants (46). Previous studies established the pathological significance of these genes in Pseudomonas syringae pv. phaseolicola, the casual agent of halo blight disease in bean plants (27). Most of the hrp genes in this bacterium lie in a -22-kb region (the hrp cluster), which is chromosomally located and genetically composed of seven complementation groups, hrpL, hrpAB, hrpC, hrpD, hrpE, hrpF, and hrpRS (39) (see Fig. 1). An additional hrp gene, hrpM, is unlinked to this cluster (12). Several investigators have described genes with similar or analogous functions in phytopathogenic gram-negative bacteria that represent four major taxa: P. syringae, Pseudomonas solanacearum, Erwinia spp., and Xanthomonas campestris (6,7,26,35,44) In this study, we investigated the nature and role of physiological factors involved in the transcriptional regulation of the hip genes of P. syringae pv. phaseolicola by using chromosomally located hrp: :inaZ fusions in complemented and noncomplemented strains grown in planta and in vitro. Our studies show that expression of the hrp genes is controlled by a specific plant signal(s), pH, osmolarity, and the nature of the carbon source. The biological significance and the mechanistic implications of these diverse physicochemical inputs in hip gene expression are critically discussed, and a hypothesis concerning the sequence of events which take place early in the plant-bacterium interaction is proposed. MATERIALS AND METHODSMedia, reagents, and growth conditions. P. syringae pv. phaseolicola NPS3121 and all its derivatives were routinely grown at 24°C in King's B medium (21) or in modified King's B medium lacking glycerol as specified in the text and legends. Defined mineral salts media were made by adding various carbohydrates, amino acids, and organic acids from concentrated, filter-sterilized stocks to M9-salts medium (28). Except as otherwise stated in the text and legends, (i) the carbon source used in M9 medium was sucrose and (ii) the final concentrations of carbon sources or other individual supplements were 5 mM and the pH was adjusted to 5.5. Final concentrations of antibiotics in the media were 15, 20, 50, and 100 ,ug/ml for tetracycline, spectinomycin, nalidixic acid, and rifamycin, respectively.Transfer from nutritionally complex to defined M9 medium caused a variable growth lag in the cultures depending on the carbon source present in the M9 medium. To minimize this lag, the carbon substrate present in the M9 medium 3499 JOURNAL