Innate Immune Regulation
Immune responses need to be tightly regulated to provide effective protection against infectious threats, but at the same time avoid overwhelming inflammatory reactions. How immune cells achieve this balance at the subcellular level is the overall focus of our research. We are taking a cell biological approach to study how the spatial organization and trafficking of innate immune receptors contributes to immune homeostasis and how perturbations of these processes promote inflammation and autoimmunity. To address these questions we are using a combination of advanced imaging techniques, genome-editing and state-of-the-art protein perturbations, biochemical assays, and in vivo models.
Nucleic acid-sensing Toll-like receptors
Receptors of the innate immune system recognize conserved microbial features and provide key signals to initiate an immune response. Multiple transmembrane and cytosolic immune receptors have evolved to recognize RNA and DNA, including members of the Toll-like receptor (TLR) family. Nucleic acid sensing enables the recognition of a broad range of pathogens, however, it also exposes the host to potential self-recognition and autoimmunity. A key mechanism to limit self-recognition by TLRs is their intracellular localization within late endosomes; compartments that are poorly accessed by self-nucleic acids. Although endosomal localization is essential for proper self/non-self discrimination, very little is known about the actual spatial organization of TLRs and which transport mechanisms and membrane interactions regulate receptor trafficking to these compartments. We want to map the precise locations of nucleic acid-sensing TLRs in high-resolution and identify the specific endosomes, in which ligand sensing and signaling occurs. We have previously shown that TLR7 (RNA sensor) and TLR9 (DNA sensor) are quite differently regulated within the endosome, opening up the possibility that these two receptors could signal from functionally distinct subsets of endosomes; an idea we are actively exploring. We also employ genetic tools to probe how altered TLR localization and trafficking influences immune responses and self/non-self discrimination.
Late endosomes/lysosomes are very motile organelles that move along microtubule tracks to either occupy the perinuclear region or the periphery of a cell. Endosome location is critical for many biological processes and perturbation of endosome positioning contributes to the pathogenesis of various diseases, such as cancer, neurodegeneration and autoimmunity. We seek to understand how endosome positioning influences the signaling choices and immune behavior of nucleic acid-sensing TLRs. Through a variety of genetic and chemical-induced approaches we target proteins involved in the movement and positioning of endosomes to dissect how TLRs operate within the complex endosomal infrastructure. Our goal is to understand how immune receptor organization at the subcellular level relates to inflammatory and autoimmune diseases.