Research Program

Our research investigates how the physiological environment shapes human immunity, particularly through its effects on cellular metabolism. We study these processes in the setting of critical illness, where rapid changes in oxygen availability, nutrient supply, and inflammatory signaling place extraordinary demands on immune cells. This allows us to explore fundamental questions about immune regulation while investigating the mechanisms of dysfunction in human disease.

Context-Specific Regulation of Immunity and Metabolism

The mechanisms that immune cells depend on are not necessarily the same in every environment. Pathways that are dispensable under homeostatic conditions may become essential during physiological stress. Understanding these changing requirements is central to our research.

We investigate how metabolic and environmental challenges influence immune cell survival, differentiation, and function. Using primary human immune cells, we examine the consequences of mitochondrial stress, altered nutrient availability, and other conditions relevant to critical illness. Targeted experimental perturbations, metabolic flux measurements, and isotope tracing help us identify the pathways that support cellular adaptation and determine when these responses become dysfunctional.

Immune Cell States and Dynamics in Critical Illness

Critical illness profoundly alters the immune system, but these changes are neither uniform across cell populations nor constant over time. Some responses may help immune cells adapt to stress, while others may contribute to persistent dysfunction. Distinguishing these processes requires understanding the diversity and evolution of immune responses in patients.

We use longitudinal ICU cohorts, single-cell transcriptomics, and high-dimensional flow cytometry to examine how immune cell populations and functional states change during sepsis and other critical illnesses. By integrating these findings with metabolic measurements and clinical data, we investigate the biological mechanisms underlying immune heterogeneity and their relationships to disease severity and outcomes.

Novel In Vivo Approaches to Understanding Human Immunometabolism

Cellular metabolism is influenced by the physiological environment of the whole organism. Understanding how immune cells use nutrients in living humans therefore presents questions that cannot be fully addressed through isolated cell experiments.

We are developing approaches to measure metabolic activity directly in human immune cells in vivo. Our TORCH platform uses stable isotope-labeled glucose to trace nutrient metabolism in circulating immune cells. Combined with metabolomics and cell-specific analyses, these studies offer opportunities to investigate how immune metabolism varies across physiological conditions and to connect experimental findings with metabolic processes occurring in the human body.

Metabolic Resuscitation in Critical Illness

Metabolic dysfunction is a prominent feature of critical illness, but its consequences for immune function remain incompletely understood. Changes in nutrient availability and cellular metabolism may represent adaptive responses, contribute to dysfunction, or both.

We investigate how modifying the metabolic environment influences human immune cell function and whether these effects depend on cellular state or physiological context. Our work draws on mechanistic experiments and samples from clinical studies of metabolic interventions, including ketone supplementation. Through these approaches, we seek to understand when metabolic changes support immune function and whether restoring specific metabolic processes can improve cellular responses during severe illness.