The Bailis lab aims to understand how human health is impacted by organismal and immune cell metabolism. We do so by leveraging in vitro and in vivo CRISPR/Cas9 screening systems compatible with gene editing in primary human and mouse immune cells.
Together with next generation sequencing and metabolomics, this permits us to fully interrogate how metabolic networks control immune cell function. Our work is currently focused in three major areas:
How does spatial compartmentalization of metabolism regulate immune cell state?
Multicellular eukaryotes compartmentalize metabolic information at multiple levels. Within cells, biochemical reactions are separated by the organelles within which they occur; within tissues, metabolites can be divided between the cells that compose them; within an animal; different organ systems generate and consume distinct metabolic products that are shared throughout their host.
Taking advantage of organelle tagging technologies that allow us to purify immune cell nuclei, ribosomes, and mitochondria from heterogeneous tissues, we aim to elucidate how this biochemical partitioning influences cell programming, tissue patterning, and disease outcome.
How does biochemical state control immune cell signaling?
In the context of immune cell activation, cellular metabolism is often understood to be one of many biological processes regulated downstream of classic signal transduction.
From this top-down view, metabolism is a passive participant in cell reprogramming, acted upon by signaling pathways. There is now a large body of literature illustrating that metabolism can also act in a bottom-up fashion to regulate both signaling effectors as well as epigenetic modifications on the histones that control gene expression.
In this manner, the biochemical potential of a cell has the capacity to tune both the quality and quantity of signaling that occurs as well as how that signal is received at target genes in the nucleus. We are actively investigating how signaling relays information through metabolism and how metabolism in turn influences the activity of signaling proteins.
How do inborn errors of metabolism impact the immune system?
Inborn errors of metabolism (IEM) are a group of rare genetic disorders that prevent the body from metabolizing food or removing nutrient waste. These defects result in a failure to produce certain essential nutrients or a toxic buildup of metabolites that can cause developmental delays, organ failure, and wasting. While IEM are traditionally not thought of as immunodeficiencies, many individuals with IEM display hallmarks of immune dysfunction, including recurrent and longer lasting infections.
Working at Children’s Hospital of Philadelphia, we have the privilege to collaborate with doctors who work with these patients and their families. The goal of our work is to better understand how IEM alter immune cell function, in hopes of improving the care of patients with IEM and learning more broadly how the immune system can be modulated by metabolism.
We do so by: 1) working directly with immune cells from IEM patients; 2) modeling the mutations found in these patients using CRISPR/Cas9 engineering of primary human immune cells; 3) performing in vivo infection and vaccination studies with genetic mouse models of these diseases.