Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY/ABTRACT This proposal presents a five-year research career development plan focused on improving diagnosis of post-traumatic sepsis using microbial DNA sequencing in plasma. I am an Assistant Professor of Surgery at the University of Wisconsin-Madison, with previous clinical and research experience in trauma surgery, patient- centric predictors of sepsis, and lab-based genomic analyses of plasma in patients with sepsis. I have assembled an outstanding mentorship team with expertise in infectious disease, cell-free DNA, genomic data analysis, and bioinformatics. The proposed training will enhance my development across the disciplines of translational research, laboratory and computational methods in genomics, and scientific writing. This will enable me to transition to research independence as a surgeon-scientist dedicated to improving outcomes for trauma patients with sepsis by developing better diagnostic tests based on microbial genomics. Sepsis is a life-threatening condition, estimated to cause one-fifth of all deaths worldwide. Approximately 25% of trauma patients develop sepsis during their hospital course and more than 20% of such patients die during the same hospitalization. Sepsis, if not recognized and treated early, may evolve into septic shock and multiple organ failure. Thus, the treatment of sepsis emphasizes timely initiation of antibiotics and source control in surgery/trauma patients. However, the diagnosis of sepsis in patients with traumatic injury is complicated because systemic inflammatory response to injury mimics sepsis. In the current paradigm, confirmation of sepsis is based on clinical signs, laboratory and radiographic findings, and medical scores which are usually obtained after sepsis onset. There are approximately 200 biomarkers of sepsis described in literature but nearly all such biomarkers rely on measuring inflammatory response, which is confounded in patients with trauma. Recent studies, including my preliminary work, have shown that metagenomic sequencing of plasma DNA can rapidly identify pathogens in patients with clinical suspicion of sepsis but these assays have not been investigated in trauma patients. To address this gap, I propose to develop and evaluate a metagenomic sequencing-based assay for analysis of microbial DNA shed into the blood. My central hypothesis is that quantitative analysis of microbial DNA levels in trauma patients can predict sepsis, rapidly identify the causative organism of sepsis, and help decrease the duration of antimicrobial treatment. Using prospectively collected plasma samples from trauma patients, I propose the following aims: 1) To determine if an increase in circulating microbial DNA levels is predictive of sepsis in trauma patients, 2) To assess concordance between causative organism identified using standard-of-care microbiology and detection of pathogen-specific DNA in plasma, and 3) To evaluate circulating microbial DNA levels in plasma as a biomarker for monitoring antimicrobial response.
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