BLRD Research Career Scientist Award Application

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Sepsis remains the leading cause of hospital mortality today. Despite its increasing incidence due to an aging population with greater comorbidities, in-hospital mortality from sepsis has significantly declined over the past decade. This decline in mortality is due in large part to earlier recognition and better compliance with best practices in early sepsis management. Despite decreased in-hospital mortality, a large fraction (up to 50% in some studies) of sepsis survivors never fully recover and develop chronic critical illness – characterized by persistent immune suppression, recurrent infections, sepsis recidivism, and poor long-term outcomes. The applicant of this BLRD Merit Review Research Career Scientist (RCS) Award is Thomas S. Griffith, Ph.D., a Research Health Science Specialist at the Minneapolis VA Health Care System (MVAHCS) currently supported by two VA Merit Awards (I01 BX001324-10 and I01 BX001324-01). Dr. Griffith is also a Professor (with tenure) in the Department of Urology at the University of Minnesota, serving as PI on two NIH grants (1R35 GM140881-01 and 1R21 AI154527-01) and co-investigator on a third NIH grant (1R01 CA260825-01). Over the past 12 years, the applicant’s laboratory has been investigating sepsis-induced immune suppression using a combination of multiple preclinical models and human samples. Current preclinical research activities in the applicant’s laboratory leverage a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections to train the immune system for robust responses to new pathogens. Environmental pathogen exposure is one important difference between basic human and laboratory mouse biology that must be considered when using mice 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 infection and vaccination experienced. While specific pathogen-free (SPF) housing of laboratory mice has been instrumental in increasing experimental reproducibility, it has simultaneously further distanced the mouse as a model from humans largely because SPF mice live their lives with limited microbial exposure. Thus, the over-arching goal of the research performed in Dr. Griffith’s laboratory is to study how changing the “starting point” of the immune system (i.e., mature, adult-like immune system of ‘dirty’ mice that have experienced physiological microbial exposure vs. naïve, neonate-like immune system of SPF mice) influences the magnitude of the acute innate immune response to a septic event. Moreover, the work being done may also help to address the important fact that there is a lack of successful treatments for humans with sepsis. Over 100 agents (many targeting cytokines) with preclinical efficacy in mouse models of sepsis have been unsuccessful in humans, making it tempting to speculate the exclusive use of SPF mice in previous preclinical studies may have underestimated the magnitude of the sepsis-induced cytokine storm and/or pathophysiology. It is expected that comparing the extent of immune dysfunction during sepsis in microbially-experienced ‘dirty’ mice to human samples will help to validate the clinical relevance of this novel mouse model that mimics this critical aspect of human biology – exposure to multiple infectious pathogens that generates an experienced immune system – to serve as an important addition to the preclinical toolbox for studying sepsis. An key component of the work performed is the expectation of making the research discoveries available to other researchers and clinicians to help inform the development and testing of new treatment options to improve the health needs of our nation’s Veterans who have experienced a septic event. It is the applicant’s goal to use this RCS award to help him put the applicant’s laboratory in the position to continue this trajectory towards clinical translation of important insights in sepsis pathophysiology gained from basic biomedical research.