Thirumala-Devi Kanneganti

Thirumala-Devi Kanneganti is an immunologist and one of the founding scientists of the inflammasome field, ranked among the top researchers in innate immunity. She is the Vice Chair of the Department of Immunology, Director of the Center of Excellence for Innate Immunity and Inflammation and holder of the Rose Marie Thomas Endowed Chair at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer. She then received her M.Sc. and PhD from Osmania University in India. She then went on to do postdoctoral fellowships at the University of Wisconsin and the Ohio State University studying fungal genetics and plant innate immunity. In 2022, she also became the Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude.

Kanneganti's early discoveries were foundational in the inflammasome field, providing the first genetic evidence for NLRP3 inflammasome activation in response to microbial components and live pathogens. ZBP1, Vince Kidd Memorial Mentor of the Year Award (2015) American Society for Microbiology Eli Lilly and Company-Elanco Research Award (2017) Fellow in the American Academy of Microbiology, American Society for Microbiology (2021) Outstanding Scientist Award, AAIS in Cancer Research (2022) Rosalind Franklin Society Special Award in Science (2023) Fellow in the American Association for the Advancement of Science (AAAS) (2023) American Association of Immunology-Thermo Fisher Meritorious Career Award (2024)

Major contributions The NLRP3 inflammasome, conceptualization of PANoptosis, discovery of PANoptosomes Kanneganti has made discoveries elucidating the roles of innate immune receptors and inflammasomes, advancing the understanding of inflammation and inflammatory cell death. Her work has clarified the role of NLRP3 in inflammasome formation and has expanded the understanding of various inflammasome pathways. Her studies, along with those from other groups published in 2006, provided the first genetic evidence for the role of NLRP3 in the formation of the inflammasome, caspase-1 activation, and IL-1β/IL-18 maturation. These initial studies showed that microbial components, ATP, and MSU crystals activate the NLRP3 inflammasome.

Kanneganti discovered that Influenza A virus, Candida, and Aspergillus specifically activate the NLRP3 inflammasome and elucidated the physiological role of the NLRP3 inflammasome in host defense. Beyond infectious diseases, her lab also established the importance of the NLRP3 inflammasome in autoinflammatory diseases, intestinal inflammation, neuroinflammation, cancer,

Kanneganti's lab has also worked on the upstream regulatory mechanisms of NLRP3 and inflammasome-induced inflammatory cell death, pyroptosis. Her lab identified caspase-8 and FADD as key regulators of the expression and activation regulators of both the canonical and non-canonical NLRP3 inflammasome and pyroptosis. Her group also characterized redundancies between caspase-1 and caspase-8 and between NLRP3 and caspase-8 in autoinflammatory disease and linked diet and the microbiome to these processes. These studies demonstrated that the NLRP3 inflammasomepathway is closely connected to caspase-8–mediated cell death. This led Kanneganti to characterize ZBP1 as a regulator of PANoptosis, a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes. PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer. The RIPK1-PANoptosome responds to Yersinia infection and the inhibition of transforming growth factor beta-activated kinase 1 (TAK1), a molecule Kanneganti identified as a master regulator that maintains cellular homeostasis by negatively regulating the NLRP3 inflammasome and inflammatory cell death. The NLRC5-PANoptosome responds to the combination of heme, PAMPS or TNF, as well as depletion of NAD+. The NLRP3-PANoptosome contains the NLRP3 inflammasome as an integral component and responds to canonical NLRP3 inflammasome stimuli. regulates the activation of several PANoptosomes.

Overall, work from Kanneganti's lab has implicated PANoptosis in infectious, metabolic, hemolytic, neurologic, and autoinflammatory diseases and cancer. Kanneganti's lab demonstrated that the AIM2-PANoptosome is essential during herpes simplex virus 1 (HSV1) infections. Her research group also recently discovered the role of NINJ1, a key executioner of inflammatory cell death, in mediating PANoptosis following heat stress and infection, thereby identifying NINJ1 and PANoptosis effectors as potential therapeutic targets.

Cancer Beyond infectious disease and inflammatory syndromes, Kanneganti's group has also found that activating PANoptosis could be beneficial to eliminating cancer cells. Treatment of cancer cells with PANoptosis-inducing agents TNF and IFN-γ can reduce tumor size in preclinical models.

Hematological disorders Dr. Kanneganti's work has also revealed the role of PANoptosis in hematologic disorders. Her research identified that NLRC5- and NLRP12-mediated PANoptosis is activated by heme, which can be released during red blood cell lysis in infections or inflammatory diseases. The deletion of NLRP12 was shown to protect against pathology in animal models of hemolytic diseases, positioning NLRP12 as a potential therapeutic target. Additionally, her lab discovered the NLRC5-PANoptosome's response to NAD+ depletion, triggered by heme-containing stimuli, and demonstrated that NLRC5 deletion provides protection not only in hemolytic disease models but also in colitis and hemophagocytic lymphohistiocytosis (HLH) models. She identified the role of the IL-1α and RIPK1/TAK1/SYK signaling pathways in skin inflammation. Overall, Kanneganti's lab discovered distinct and previously unrecognized functions of the cytokines IL-1α, IL-1β, and IL-33 and their signaling pathways in inflammatory diseases and cancer.

Beyond her studies on IL-1 family members, her recent work on cytokine storm established TNF and IFN-γ as the key upstream cytokines that cause inflammatory cell death (PANoptosis), tissue and organ damage, and mortality, and she has suggested that strategies to target these cytokines or other molecules in their signaling pathway should be evaluated as therapeutic strategies in COVID-19, sepsis, and other diseases associated with cytokine storm.