Investigating inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer
Innate immunity is the first line of defense against infectious disease. The resulting inflammation is the first response to infection and injury. Pathogen sensing and signaling in innate immune and barrier cells drive inflammation to combat infection. Excessive or chronic inflammation can contribute to the development and many diseases including autoimmune disorders and cancer. Our laboratory seeks to gain fundamental insight into innate immune mechanisms to identify novel processes and new molecular targets. This will inform the development of therapeutic strategies.
Our laboratory is known for fundamental discoveries elucidating functions of innate immune receptors, inflammasomes, and inflammatory cell death. As a founding member of the inflammasome field, we continue to make critical contributions to this research area. The inflammasome, a multimeric protein complex, is a critical component of the innate immune response. Inflammasomes sense pathogen- and damage-associated molecular patterns to initiate inflammatory immune responses and drive pyroptosis, a form of programmed cell death. While cell death is essential for organismal development, dysregulation often leads to disease.
We provided the first genetic evidence for the role of the innate immune receptor NLRP3 in microbial-mediated inflammasome activation. We also established the importance of the NLRP3 inflammasome in intestinal inflammation, neuroinflammation, cancer, and metabolic diseases. We have continued to provide innumerable insights to drive the maturation of this field into a major research area by identifying key components and regulatory mechanisms of inflammasome pathways and discovering their biological and physiological functions. Beyond our work on the NLRP3 inflammasome and cell death pathways, we have identified the activation mechanisms of other inflammasomes including NLRC4, NLRP1, PYRIN, and AIM2 in infection, inflammatory disease, and cancer Additionally, we have identified the activation mechanisms of other inflammasomes; characterized other key innate sensing pathways; and described distinct, novel roles for IL-1α, IL-1β, and IL-33 in disease.
These studies on inflammasomes/pyroptosis led to a pivotal breakthrough in the cell death research area. Pyroptosis, apoptosis, and necroptosis represent three key programmed cell death processes originally thought to be distinct. However, we have found extensive crosstalk among them, leading us to establish the fundamental concept of PANoptosis and this new field of research. PANoptosis is defined as a unique, physiologically relevant, inflammatory programmed cell death pathway activated by specific triggers and regulated by the PANoptosome complex. The PANoptosome provides a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and necroptosis. The ability of these molecules to interact supports the intricate and nuanced coregulation among cell death pathways that had previously been thought to be independent.
We identified ZBP1 as the first innate immune sensor to form a PANoptosome and induce PANoptosis. Building on this initial discovery, our work has elucidated several infectious agents, cytokine signaling pathways, and inflammatory syndromes that activate PANoptosis, implicating this process in infectious and autoinflammatory diseases, cancer, and beyond. Recently, we discovered that TNF and IFN-γ released during disease, specifically during COVID-19, drive PANoptosis to induce further cytokine release, tissue damage, and death, providing the first mechanistic definition for cytokine storm.
Overall, with more than 290 manuscripts, all focused on innate immunity, inflammasomes, and cell death, our studies have contributed to both the inception and the maturation of the inflammasome field as a major research area in immunology and inflammation research, advanced our understanding of cell death pathways, progressed new therapeutics, and identified novel applications for existing drugs.
Dr. Thirumala-Devi Kanneganti began her career in research as a PhD student studying plant pathogens and fungal toxins. She went on to do postdoctoral fellowships at the University of Wisconsin and the Ohio State University studying fungal genetics, plant innate immunity, and a form of plant cell death called the hypersensitive response. She then transitioned to study mammalian innate immunity at University of Michigan. From there, Dr. Kanneganti joined St. Jude as an Assistant Member in the Immunology Department in 2007, where she has focused on studying inflammasomes and inflammatory cell death in innate immunity, infections, inflammatory diseases, and cancer. She became a full Member in 2013 and Vice Chair of the Immunology Department in 2016. Dr. Kanneganti was then endowed with the Rose Marie Thomas Endowed Chair in 2017.
Interdisciplinary team of immunologists, cell and molecular biologists, microbiologists, and cancer biologists