The tiny machines of immunity.
Our lab investigates the molecular mechanisms that underpin the antibody-based cellular immune response. Our goal is to establish new paradigms to inform the design of therapeutics for a range of human diseases.
Molecular Biology of the Immune Synapse
MINFLUX nanoscopy is a super-resolution fluorescent microscopy technique that stems from the Nobel Prize winning technologies of PALM/STORM and STED, enabling rapid tracking and 1-3 nanometer resolution localization of single molecules in the cellular environment. We are developing protocols to tailor MINFLUX for studying Fc gamma receptors within Natural Killer cell immune synapses formed with virally infected cells. Determining how antibodies influence immune synapse dynamics could shed light on the molecular basis of differential antibody effector activity and form new paradigms to inform the design of therapeutics with enhanced potency toward a broad range of human diseases.
Structural Biology of Antibody Receptors
Omics data of antibody-mediated cellular activation
The way the immune system reacts to pathogenesis is not uniform and is different depending on the insult. When white blood cells are activated to control a threat, the resulting transcriptional signature of those cells is uniquely associated with the nature of the threat and the type of cytotoxicity required. Antibodies can also activate effector cells, but are not uniform in the type and potency of activity. We hypothesize that antibody phenotype (i.e. epitope, glycosylation, isotype, angle-of-approach) may influence effector function. Using functional drug screens and next-generation RNA sequencing methods, we hope to define genes and pathways that differentially respond to antibody phenotype and uncover ways to regulate cellular cytotoxicity to augment antibody and cellular therapeutics.
Previous we have used structural biology techniques, primarily single particle cryo-electron microscopy, to examine how protective and broadly neutralizing antibodies bind to viral antigens. These structures also provide a large database of structures across multiple viral antigens (HIV, influenza, ebolaviruses) that show the variety of immune complex geometries that can form on the surface of virally infected cells. Using structural biology, we plan to study how these immune complex geometries influence the molecular arrangement of Fc gamma receptor activation complexes.
