Understanding carnitine reprogramming in sepsis

/ABSTRACT Sepsis is a syndrome of physiologic dysregulation and multiorgan dysfunction resulting from infection. According to the World Health Organization, sepsis has an annual global incidence of 50 million and mortality rate of 20-40% - accounting for 20% of global deaths. The Agency for Healthcare Research and Quality estimates that sepsis accounts for over $50 billion in U.S. annual healthcare expenditures (2024). Thus, there is a tremendous need for improved treatment approaches for sepsis. Dr. Eric I. Elliott’s research in the Wang lab using human samples and mouse models has revealed that: (1) adaptive regulation of carnitine metabolism in bacterial and viral sepsis promotes survival; (2) following priming by bacterial inflammation, L-carnitine activates the Pyrin inflammasome; and (3) the high-affinity L-carnitine transporter SLC22A5 is a potential target to modulate inflammation and survival. Employing the novel SLC22A5 conditional knockout mouse developed by Dr. Elliott, this proposal seeks to understand tissue-specific roles of carnitine metabolism in sepsis in order to: (1) determine how carnitine metabolic reprogramming impacts survival, (2) assess the therapeutic role of cell-specific SLC22A5-targeting, and (3) identify additional pathways and molecules that could be targeted to improve sepsis outcomes. Furthermore, as metabolomic and GWAS studies implicate L-carnitine, SLC22A5, and Pyrin in many other inflammatory diseases, the pathways and targets elucidated in this proposal may have translational relevance extending beyond sepsis. This proposal outlines a rigorous five-year training program for Dr. Eric I. Elliott, MD, PhD, to prepare him for his independent research career. The principal investigator, Dr. Elliott, is a physician-scientist who completed his MD/PhD training at the University of Iowa where he studied the regulation of inflammasome activation by mitochondrial cardiolipin. He completed his internal medicine residency and infectious disease fellowship in the Yale Physician-Scientist Training Program, and is currently an Instructor in the Section of Infectious Diseases at Yale. He joined the laboratory of Dr. Andrew Wang, MD, PhD, to study the metabolic adaptations in sepsis. Dr. Wang is an experienced mentor and expert in neuro-endocrine-immune interactions in homeostasis, stress, and inflammation. This proposal will provide Dr. Elliott with additional scientific and technical expertise in assessing mitochondrial metabolism, microscopy, RNA sequencing, and translational genetics research pertinent to the planned research and its future applications. Furthermore, Dr. Elliott will receive training in scientific communication, writing, and laboratory management. He will complete his research and training objectives with the tremendous support and resources provided by the Yale Department of Internal Medicine (Section of Infectious Diseases), the mentorship of Dr. Andrew Wang, and the guidance of his strategically assembled advisory committee. Successful completion of the proposed research and training will ensure Dr. Elliott attains his goal of becoming a leader in the field of inflammation-induced metabolic reprogramming. Project Number: 1K08AI196242-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Eric Elliott | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $194,904 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 IIDA-N (82)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08AI19624201