Thirumala-Devi Kanneganti

Thirumala-Devi Kanneganti (born 18 October 1972) is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. Her research interests include innate immunity and inflammatory cell death with a primary focus on the role of NLR proteins and inflammasomes in health and disease.
Early life and education.
Kanneganti is from Kothagudem, Telangana (United Andhra Pradesh), India. She received her undergraduate degree from Singareni Collieries Women's College, Kothagudem at Kakatiya University, where she majored in chemistry, zoology, and botany. She then received her M.Sc. and PhD from Osmania University in India.
Career.
Kanneganti began her career in research as a PhD student studying plant pathogens and fungal toxins. 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. She then transitioned to study mammalian innate immunity at the University of Michigan. She joined St. Jude Children's Research Hospital as an Assistant Member in the Immunology Department in 2007, where she has focused on studying inflammasomes and cell death. She was promoted to a full Member in 2013. She became Vice Chair of the Immunology Department in 2016 and was endowed with the Rose Marie Thomas Endowed Chair in 2017.
Major contributions.
Discovery of NLRP3 inflammasome and PANoptosis as therapeutic targets for infectious and inflammatory diseases and cancer.
Kanneganti is well known for her breakthrough discoveries elucidating functions of innate immune receptors, inflammasomes, and inflammatory cell death and for making fundamental contributions to inflammasome biology. 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. In addition to these studies on the role of the NLRP3 inflammasome in infectious diseases, her lab also established the importance of the NLRP3 inflammasome in autoinflammatory diseases, intestinal inflammation, neuroinflammation, cancer, and metabolic diseases.
Kanneganti's lab has also been working on the upstream regulatory mechanisms of NLRP3 and inflammasome-induced inflammatory cell death, pyroptosis. Her lab identified caspase-8 and FADD as expression and activation regulators of both the canonical and non-canonical NLRP3 inflammasome/pyroptosis. This study demonstrated that the NLRP3 inflammasome/pyroptotic pathway is closely connected to the caspase-8–mediated programmed cell death pathway. This finding went against the dogma that existed at that time that caspase-8 and FADD were involved only in the apoptotic pathway.
Following up on her original discovery that NLRP3 senses viral RNAs, her lab has discovered Z-DNA binding protein 1 (ZBP1)/DAI as an innate sensor of influenza virus upstream of the NLRP3 inflammasome/pyroptosis and also showed ZBP1 is a key regulator of apoptosis and necroptosis, establishing it as a master regulator of these cell death pathways.
Her lab also established that transforming growth factor beta-activated kinase 1 (TAK1) can act as a master regulator that maintains cellular homeostasis by negatively regulating the NLRP3 inflammasome and pyroptosis, apoptosis, and necroptosis. Overall, these studies identified caspase-8, ZBP1, and TAK1 as master molecular switches of inflammasome activation/pyroptosis, apoptosis, and necroptosis and pioneered the establishment of the fundamental concept of PANoptosis (Pyroptosis; Apoptosis; Necroptosis; 'optosis', a form of programmed cell death).
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. Kanneganti's research group recently further elucidated the molecular mechanism of PANoptosis and showed that the enigmatic caspase-6 is critical for ZBP1-mediated NLRP3 inflammasome activation, PANoptosis, innate immune responses, and host defense against IAV. Her lab also showed that coronavirus activates PANoptosis and that inhibiting the NLRP3 inflammasome or gasdermin D during coronavirus infection actually increases cell death and cytokine secretion rather than decreasing them.
Her group went on to discover the role of PANoptosis in cytokine storm, identifying TNF and IFN-γ as key cytokines that cause this inflammatory cell death pathway and lead to lung damage, organ failure, and lethality. Kanneganti's research group also showed that inhibiting TNF and IFN-γ could prevent lethality in SARS-CoV-2 infection, septic shock, hemophagocytic lymphohistiocytosis, and cytokine shock in mice. This led her to advocate for the evaluation of a strategy to repurpose approved drugs that inhibit TNF-α or IFN-γ, as well as those that target other molecules in the PANoptosis pathway (e.g., JAK), to inhibit the cytokine storm and pathogenesis. Overall, work from Kannegant's lab has implicated PANoptosis in infectious, metabolic, neurologic, and autoinflammatory diseases and cancer.
Cytokine signaling and disease.
Kanneganti's lab showed compensatory roles for NLRP3/caspase-1 and caspase-8 in the regulation of IL-1β production in osteomyelitis. Additionally, discoveries from her research group suggest that IL-1α and IL-1β can have distinct roles in driving inflammatory disease. She identified the role of the IL-1α and RIPK1/TAK1/SYK signaling pathway in skin inflammation. Furthermore, her studies also showed the role of another IL-1 family member, IL-33, in regulating immune responses and microbiota in the gut. Overall, Kanneganti's lab discovered distinct and previously unrecognized functions of cytokines IL-1α, IL-1b, 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 they key upstream cytokines that cause inflammatory cell death (PANoptosis), tissue and organ damage, and mortality and suggest 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.