Ep. 47: “Structural and Mechanistic Immunology” Featuring Dr. Hao Wu
Feb 14, 2023
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Dr. Hao Wu, the Asa and Patricia Springer Professor of Structural Biology at Harvard Medical School, delves into the exciting world of innate immunity. She explains how cryo-electron microscopy has revolutionized the study of structures like the NLRP3 inflammasome and Gasdermin D. The conversation also highlights the role of AlphaFold in structural biology, revealing how lipid metabolism influences T cell function. Additionally, they discuss innovative approaches to treating peanut allergies, showcasing cutting-edge research in immunology.
Dr. Hao Wu explains how cryo-electron microscopy aids in visualizing complex structures like the NLRP3 inflammasome, enhancing our understanding of innate immunity.
The interplay between immune response and gut microbiota reveals that T-cell infiltration impacts oxygen levels, exacerbating graft-versus-host disease severity.
Research on the modulation of interferon gamma dynamics indicates that its extracellular matrix binding significantly influences systemic inflammatory responses.
Deep dives
Innate Immunity and Supermolecular Complexes
Dr. Hao Wu discusses her research on the molecular mechanisms involved in the assembly and regulation of supermolecular complexes within innate immunity. She emphasizes the importance of understanding these mechanisms for therapeutic intervention, particularly regarding inflammasomes, which play a crucial role in activating the immune response. By elucidating the structural characteristics of these complexes, Dr. Wu's work helps clarify how innate immune responses can be fine-tuned and potentially manipulated for better health outcomes. This research represents a critical intersection of structural biology and immunology, highlighting the sophisticated nature of immune regulation.
The Role of Ambient Oxygen in Graft-Versus-Host Disease
A recent study highlights the relationship between ambient oxygen levels, microbiome dysbiosis, and the severity of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. The findings suggest that T-cell infiltration in GVHD disrupts intestinal epithelial cells' ability to utilize oxygen, thereby increasing oxygen levels in the gut and fostering an environment for dysbiosis. This dysbiotic microbiome, in turn, leads to exacerbated symptoms of GVHD. Interventions that normalize oxygen levels or restore a healthy microbiome can mitigate the severity of GVHD, demonstrating a critical interplay between immune response and gut microbiota.
Interferon Gamma Binding to Extracellular Matrix
A study explores the role of interferon gamma (IFNg) in modulating systemic toxicity through its binding to the extracellular matrix. The research identifies a conserved C-terminal domain of IFNg that facilitates its attachment to heparan sulfate moieties in the extracellular matrix, thereby influencing its stability and distribution. Disruption of this binding significantly increases circulating levels of IFNg, leading to heightened systemic inflammatory effects without altering its local immune functions. These insights inform potential therapeutic strategies targeting IFNg dynamics to control inflammatory responses effectively.
Phospholipid Saturation in T-Cell Function
Research reveals that the saturation levels of phosphatidylinositol phosphates play a pivotal role in the signaling and functionality of CD8 effector T cells. The study demonstrates that higher concentrations of saturated PIPs during T cell activation enhance effector functions, thereby linking fatty acid metabolism to immune responses. Knockdown of enzymes responsible for the synthesis of these saturated lipids results in impaired T cell performance. This connection underscores the importance of lipid biochemistry in shaping immune cell behavior and responses against tumors.
Peanut Allergies and Innovative Treatments
A promising approach to treating severe peanut allergies involves a peanut allergen-specific inhibitor that prevents anaphylaxis in humanized mouse models. This dual-action molecule binds to IgE antibodies, blocking their interaction with peanut allergens and thereby inhibiting mast cell activation. Experiments show significant reduction in allergic responses when the inhibitor is administered before or even after allergen exposure. These findings pave the way for potential therapeutic options for managing peanut allergies, highlighting the need for innovative allergy treatments in clinical settings.
Dr. Hao Wu is the Asa and Patricia Springer Professor of Structural Biology at Harvard Medical School. Her lab focuses on the molecular and cellular mechanisms that govern the assembly, regulation, and therapeutic intervention of supramolecular complexes in innate immunity. She talks about cryo-electron microscopy and how her team used it to study the structures of the NLRP3 inflammasome disc, the B cell antigen receptor, and the Gasdermin D pore. She also discusses the role of AlphaFold in structural biology research.
