Investigating the effects of environmental microbial exposure on the sepsis-induced immune response
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Sepsis, a life-threatening organ dysfunction caused by dysregulated host immune response to infection, is one of the leading causes of death within intensive care units (ICUs) in the United States. Developing specific therapies to treat sepsis is a current challenge for translational research, where over 100 drugs developed to target pro- and anti-inflammatory pathways in sepsis have failed to pass clinical trials. The recent challenge in translating effective sepsis pharmaceuticals from animals to humans has led some researchers to question the overall viability of using specific pathogen free (SPF) mice as an animal model for sepsis in human beings. SFP mice are raised in a barrier facility designed to prevent exposure to specific pathogens, while humans are exposed to a wide range of pathogens on a daily basis. Acknowledging the influence that prior environmental pathogen exposure has on the immune system’s response to future infections, researchers have developed the cohoused (CoH) mouse model as a potential alternative to SPF mice for use in research on immunological diseases such as sepsis. CoH mice are SPF mice cohoused with “dirty” pet store mice for 60 days, which increases their pathogen exposure and results in mice with immune experience more comparable to humans. Although the CoH model shows promise, a recent study conducted by Huggins et al shows increased sepsis-induced morbidity and mortality of CoH mice compared to SPF mice when using the lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) models of sepsis. The experiments described in this thesis aim to further compare the inflammatory response of SPF, CoH, and pet store mice after intra-peritoneal injections of either LPS or cecal slurry (CS) to identify potential differences among these mouse groups and better understand why CoH mice experience increased mortality during sepsis. A baseline experiment was performed on each of these mice groups for comparison. Our baseline experiments demonstrate significant elevations in peritoneal immune cells within CoH mice compared to SPF mice. CS experiments demonstrate a significantly higher infiltration of immune cells in CoH mice following cecal slurry injection compared to SPF mice, suggesting that environmental pathogen exposure influences host inflammatory response within the peritoneum. However, LPS experiments were largely inconclusive. No significant differences were observed between SPF and CoH mice in regard to immune cell infiltration within the peritoneum, while blood analysis showed significant elevations in Tumor Necrosis Factor alpha (TNFa) and Interleukin 6 (IL-6) with increasing environmental pathogen exposure. Since the inflammatory response within the peritoneum to LPS was not significantly different between SPF and CoH mice, future studies could expand upon these results by investigating other tissue compartments in SPF and CoH mice following LPS injection into the peritoneum to provide a more complete comparison between these mice during LPS induced sepsis.