Profiles

The O'Sullivan lab takes a collaborative interdisciplinary cyclical translation approach to discover new therapeutics that harness the power of the immune system. Starting with clinical datasets, we model cell-cell interactions and critical gene regulatory networks to understand the main mechanisms that drive disease during cancer, obesity, viral infection, and tissue injury. We then model these mechanisms using clinically relevant mouse models to discover conserved pathways that can be either drugged or engineered to enhance immune function. We focus on 3 fundamental research questions that have resulted in groundbreaking discoveries:

1. What are the critical gene regulatory networks in human innate immunity?

Although decades of research using mouse models have contributed to our understanding of the innate immune system, many findings in mice do not translate to humans. Furthermore, transcriptomics experiments in human innate immune cells suggest that the pathways induced in response to pro-inflammatory signals can be distinct from those in mice. These findings suggest that there is a pressing need to understand the molecular mechanisms that regulate human innate immunity. Our research program is designed to address this need through targeted CRISPR screens and bioinformatic analyses of patient samples.

2. What are the mechanisms that regulate the lifespan of innate immune cells?

Natural Killer (NK) cells are unique in that they share attributes of both the innate and adaptive immune system. NK cells can undergo clonal proliferation, contraction, and memory formation in response to viral infections such as cytomegalovirus (CMV). We are fascinated with understanding how a normally short-lived cell (~7 days) can dramatically enhance its lifespan to over a year following viral infection. Another arm of our research program is dedicated to understanding the molecular mechanisms that regulate NK cell persistence.

3. How is inflammation initiated and maintained by the innate immune system?

A complete immune response is enabled by the concerted activation of tissue-resident and circulating immune cells. However, we are only beginning to understand the role of tissue-resident immune cells in host physiology and disease. Our research interests have focused on the role of tissue-resident type 1 innate immune cells (cDC1, NK cells, ILC1) in host protection and pathology in response to pathogen-induced and sterile inflammation.