Understanding the Mechanisms of Innate Immunity
Our lab is tackling fundamental questions about immunology and immune activation that will help guide efforts in vaccine development and drug delivery design. Some of these questions include: Why are some immune cells more responsive than others? What features of an initial host-pathogen interaction are involved in initiating an immune response? To what extent does receptor clustering inform an immune cell’s activated phenotype?
Using state-of-the-art technologies such as lattice light sheet microscopy, fluidic force microscopy, and single-cell mRNA sequencing, we assay receptor-ligand interactions, macrophage-pathogen interactions, and cellular activation to elucidate mechanistic details about the immune response to stimulation. Through our studies, we hope to uncover critical features of the immune response that vaccine adjuvants and other synthetic stimulants can mimic to optimize and/or reprogram immune responses.
Red: TLR2, green: b. subtilis
1. Live Receptor Imaging
We are pioneering the study of live TLR dynamics via lattice light sheet microscopy. Through this high-speed imaging technique, we are able to directly quantify TLR dynamics in response to agonist stimulation. These studies will help uncover key insights into the physical behavior of these receptors upon activation--including how different stimulant classes, molecular assemblies, and geometries inform different receptor responses. We hope to use these findings to design vaccine adjuvants that promote strong protective responses by interacting optimally with innate immune receptor systems.
2. Single Macrophage Stimulation in Culture
FluidFM technology allows for local chemical or mechanical stimulation of target cells with minimal disturbance of their environment and simultaneous monitoring with live-cell microscopy. Traditional experiments either isolate the cells or stimulate them collectively, but with the FluidFM, we can provide a localized stimulus to an otherwise undisturbed culture. With this technique we can approximate the situation of a single macrophage in a group encountering a single pathogen or localized chemical signal, allowing us to study questions about the single cell response and group coordination that might otherwise be experimentally difficult.
3. First Responder Immune Cells
Not all immune cells respond equally to the same stimulus. Our lab is working with a subpopulation of immune cells, called first responders, that generate a disproportionately high response to immune-stimulatory microparticles. We are developing targeting liposomes loaded with immune-stimulatory TLR agonists. These liposomes will allow us to deliver their immune-stimulatory contents to the most responsive immune cells, generating a potent immune response. This method could provide a way to modulate immune responses or deliver costly ingredients to the place they will be most effective, for example for use in vaccines.
4. Studying the Mechanism of Action of Contact Allergy
Millions of people develop contact allergies to common chemicals in our environment, and our lab is working to elucidate the mechanisms of action of such allergies. Currently the main treatment for these conditions is topical steroids, which come with their own side effects if overused. Our lab is investigating how the immune system becomes sensitized to different chemicals, and we are working to discover small molecules that could be used in therapeutics to prevent or treat contact allergy.