Thirumala-Devi Kanneganti

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Thirumala-Devi Kanneganti
Thirumala-Devi-Kanneganti-1024x1024.jpg
Born
Kothagudem, India
Alma mater
Known for
  • Investigating fundamentals of innate immunity
  • Elucidating inflammasomes
  • Pioneering the concept of PANoptosis
  • Identifying molecular mechanisms of disease
Awards
  • American Association of Immunology-Thermo Fisher Meritorious Career Award (2024)
  • Fellow in the American Association for the Advancement of Science (2023)
  • Rosalind Franklin Society Special Award in Science (2023)
  • Outstanding Scientist Award, AAIS in Cancer Research (2022)
  • Fellow in the American Academy of Microbiology, American Society for Microbiology (2021)
  • Seymour & Vivian Milstein Award for Excellence in Interferon and Cytokine Research (2018)
  • Eli Lilly and Company-Elanco Research Award, American Society for Microbiology (2017)
  • Outstanding macrophage researcher Dolph O. Adams award, Society for Leukocyte Biology (2017)
  • Investigator Award from the American Association of Immunology-BD Biosciences (2015)
Scientific career
Fields Immunology
Institutions St. Jude Children's Research Hospital
Website https://www.stjude.org/kanneganti

Thirumala-Devi Kanneganti 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. [1] She is also Director of the Center of Excellence in Innate Immunity and Inflammation 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. [1]

Contents

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. [2] [3] She then received her M.Sc. and PhD from Osmania University in India. [3]

Career

Kanneganti began her career in research as a PhD student studying plant pathogens and fungal toxins. [4] 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. [2] [3] She transitioned to study mammalian innate immunity at the University of Michigan. [2] [3] 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. [1] [3] 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. [5] In 2022, she also became the Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude. [5] Kanneganti is among the most "Highly Cited Researchers" in the world due to the noteworthy impact of her findings in the fields of innate immunity, inflammation, and cell death. [1] [6] [7] [8] [9] [10]

Awards and honors

Major contributions

Discovery of NLRP3 inflammasome, ZBP1-, RIPK1-, AIM2-, NLRP12-, and NLRC5-PANoptosomes, and PANoptosis as therapeutic targets

Kanneganti has made discoveries elucidating the functions of innate immune receptors, inflammasomes, and inflammatory cell death to contribute to the inflammasome biology and cell death fields. Her work has clarified the role of NLRP3 in inflammasome formation and has expanded the understanding of various inflammasome pathways. [21] [22] [23] [24] [25] 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. [26] [27] These initial studies showed that microbial components, [21] [28] [29] ATP, [30] [31] and MSU crystals [32] 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. [21] [33] [34] [35] [36] [37] Beyond infectious diseases, her lab also established the importance of the NLRP3 inflammasome in autoinflammatory diseases, [38] intestinal inflammation, [39] neuroinflammation, [40] cancer, [14] and metabolic diseases. [41]

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 expression and activation regulators of both the canonical and non-canonical NLRP3 inflammasome/pyroptosis. [42] 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. [38] [43] [44] These studies demonstrated that the NLRP3 inflammasome/pyroptotic pathway is closely connected to the caspase-8–mediated programmed cell death pathway. [38] [42] [43] [44] This finding went against the dogma that existed at that time that caspase-8 and FADD were involved only in apoptosis. [42]

Following up on her original discovery that NLRP3 senses viral RNAs, [28] her lab discovered Z-DNA binding protein 1 (ZBP1)/DAI as an innate immune sensor of influenza virus upstream of the NLRP3 inflammasome and cell death; however, this cell death was not consistent with any of the cell death pathways characterized at that time. [22] [45] 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. [46] [47] 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. [22] [38] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59]

She then went on to establish that multiple PANoptosomes can contain different sensors and respond to different triggers:

Collectively, these studies identified ZBP1, AIM2, RIPK1, NLRP12, TAK1, and caspase-8 as master molecular switches of inflammasome activation and PANoptosis. Additionally, her group discovered that interferon regulatory factor 1 (IRF1), a critical regulator of inflammation and cell death, [64] regulates the activation of PANoptosis. [65]

Overall, work from Kanneganti's lab has implicated PANoptosis in infectious, metabolic, hemolytic, neurologic, and autoinflammatory diseases and cancer. [22] [38] [46] [48] [49] [51] [52] [53]

Viral Infections

PANoptosis is implicated in driving innate immune responses and inflammation. Kanneganti's research group identified the ZBP1-PANoptosome as crucial for host defense during influenza A virus infections, revealing its role in promoting inflammatory cell death. [52] Her lab also showed that coronavirus activates PANoptosis and that inhibiting the NLRP3 inflammasome or gasdermin D during coronavirus infection increases cell death and cytokine secretion rather than decreasing them. [66] Kanneganti's lab demonstrated that the AIM2-PANoptosome is essential during herpes simplex virus 1 (HSV1) infections. [61] Additional work in Kanneganti's lab focusing on beta-coronaviruses showed that IFN induces ZBP1-mediated PANoptosis, which causes morbidity and mortality. These findings led her team to suggest that inhibiting ZBP1 may improve the efficacy of IFN therapy for COVID-19 and impact other infectious and inflammatory diseases where IFNs cause pathology. [49] [57]

Bacterial Infections

Dr. Kanneganti has been at the forefront of exploring PANoptosis in bacterial infections. Her research identified the RIPK1-PANoptosome as a key player in Yersinia pseudotuberculosis infections. Additionally, her lab discovered that the AIM2-PANoptosome mediates PANoptosis during Francisella novicida infections [61] Her work has extended to bacterial pathogens Salmonella enterica and Listeria monocytogenes, where the loss of caspases and RIPK3 offers protection against cell death. [67] 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. [68]

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. [51] [56] [55] Her group also discovered a regulatory relationship between ADAR1 and ZBP1 that can be targeted with the combination of nuclear export inhibitors, such as selinexor, and IFN to drive ZBP1-mediated PANoptosis and regress tumors in preclinical models. [48] [69]

Hematological disorders

Dr. Kanneganti’s work has also revealed the role of PANoptosis in hematologic disorders. Her research identified that NLCR5- 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. [62] [63]

Cytokine storm, 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. [43] [44] Additionally, discoveries from her research group suggest that IL-1α and IL-1β can have distinct roles in driving inflammatory disease. [70] She identified the role of the IL-1α and RIPK1/TAK1/SYK signaling pathways in skin inflammation. [70] Furthermore, her studies also showed the role of another IL-1 family member, IL-33, in regulating immune responses and microbiota in the gut. [71] 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. [43] [70] [71] [72] [73]

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. [51]

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">RIPK1</span> Enzyme found in humans

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis, necroptosis, and PANoptosis Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.

<span class="mw-page-title-main">NLRP12</span> Protein-coding gene in the species Homo sapiens

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

<span class="mw-page-title-main">ZBP1</span> Protein-coding gene in the species Homo sapiens

Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene.

<span class="mw-page-title-main">AIM2</span> Protein-coding gene in the species Homo sapiens

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

<span class="mw-page-title-main">NOD-like receptor</span> Class of proteins

The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">NLRC5</span> Protein-coding gene in the species Homo sapiens

NLRC5, short for NOD-like receptor family CARD domain containing 5, is an intracellular protein that plays a role in the immune system. NLRC5 is a pattern recognition receptor implicated in innate immunity to viruses potentially by regulating interferon activity. It also acts as an innate immune sensor to drive inflammatory cell death, PANoptosis. In humans, the NLRC5 protein is encoded by the NLRC5 gene. It has also been called NOD27, NOD4, and CLR16.1.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.

<span class="mw-page-title-main">GSDMD</span> Protein found in humans

Gasdermin D is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs to the gasdermin family which is conserved among vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59 (Pejvakin). Members of the gasdermin family are expressed in a variety of cell types including epithelial cells and immune cells. GSDMA, GSDMB, GSDMC, GSDMD and GSDME have been suggested to act as tumour suppressors.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

<span class="mw-page-title-main">Vishva Dixit</span> Kenyan molecular biologist

Vishva Mitra Dixit is a Kenyan-American physician who is currently Vice President and Senior Fellow of Physiological Chemistry and Research Biology at Genentech.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

PANoptosis is 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 multiprotein PANoptosome complexes. The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRC5- and NLRP12-PANoptosomes, have been characterized so far.

References

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