Integrated use of genomics, metabolomics, and cytokine profiling to validate the use of 'dirty' mice to study sepsis pathophysiology

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Each year ~2 million adult Americans develop sepsis and nearly 270,000 Americans die as a result of sepsis. In the U.S. VA health system in 2009, >35,000 Veterans were hospitalized with sepsis, and ~80% survived to hospital discharge (current numbers are likely higher). Veterans also have a high rate of hospital readmission following sepsis. Hospital costs associated with treating sepsis exceed $24B/year, making it the most expensive medical condition treated in the U.S. Faced with costly and burdensome patient care, it is imperative to better understand the pathophysiologic states experienced by these patients to deliver targeted care. Mice are one of the most important tools used in biomedical research, due in part to their ability to model complex physiological systems in humans. However, environmental microbial exposure is an important difference between basic human and laboratory mouse biology that must be considered when using mouse models to evaluate immune system fitness. Humans are naturally exposed to both commensal and pathogenic microbes daily from birth, and the immune system of adult humans has been trained and shaped by each microbe. In contrast, laboratory mice are often housed under specific pathogen-free (SPF) conditions. SPF housing has been instrumental in increasing experimental reproducibility, but it has simultaneously further distanced the mouse model from humans, largely because SPF mice live their lives with limited microbial exposure. Our proposal will leverage a novel mouse model that mimics critical aspects of the human immune system – where exposure to multiple ongoing and resolved infections is the norm. We will integrate transcriptomics, metabolomics, proteomics, and cytokine profiling to define the molecular basis of the pathophysiology and resolution of sepsis. The proposed validation studies will be key for supporting the use of microbially-experienced ‘dirty’ mice in sepsis research. There are no reported direct comparisons of immune responses in dirty septic mice to human patients. We posit that direct comparison of acute response in septic patients to sepsis models in dirty mice will show a closer correlation than the comparison between human and SPF mice. It has been argued that rodent models do not resemble the pathophysiology of human sepsis, an assumption boosted by studies claiming the molecular changes observed in human sepsis are different from the ones observed in rodents. Yet, the rodent system is an invaluable tool to advance current understanding of the immune system that will produce important information to understand septic pathology and provide clues for seeking ways to ameliorate the conditions. The main concern raised about dirty mice is the potential of increased variability in the commensal and pathogenic microbes they have encountered. If one intention of new mouse models for biomedical research is to better model humans with a diverse microbial experience, then using mice with a similarly diverse microbial exposure history must be viewed as a strength. It is important to emphasize dirty mice are meant to serve as a novel complement to, rather than replace, the SPF mice typically used in sepsis research. We see dirty mice as a valuable tool for discovering new efficacious sepsis therapies that may be sensitive to the environmental perturbations after microbial exposure.