10 results on '"Apurva Kanneganti"'
Search Results
2. The Sphingosine-1-Phosphate Lyase (LegS2) Contributes to the Restriction of Legionella pneumophila in Murine Macrophages.
- Author
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Arwa Abu Khweek, Apurva Kanneganti, Denis C Guttridge D, and Amal O Amer
- Subjects
Medicine ,Science - Abstract
L. pneumophila is the causative agent of Legionnaires' disease, a human illness characterized by severe pneumonia. In contrast to those derived from humans, macrophages derived from most mouse strains restrict L. pneumophila replication. The restriction of L. pneumophila replication has been shown to require bacterial flagellin, a component of the type IV secretion system as well as the cytosolic NOD-like receptor (NLR) Nlrc4/ Ipaf. These events lead to caspase-1 activation which, in turn, activates caspase-7. Following caspase-7 activation, the phagosome-containing L. pneumophila fuses with the lysosome, resulting in the restriction of L. pneumophila growth. The LegS2 effector is injected by the type IV secretion system and functions as a sphingosine 1-phosphate lyase. It is homologous to the eukaryotic sphingosine lyase (SPL), an enzyme required in the terminal steps of sphingolipid metabolism. Herein, we show that mice Bone Marrow-Derived Macrophages (BMDMs) and human Monocyte-Derived Macrophages (hMDMs) are more permissive to L. pneumophila legS2 mutants than wild-type (WT) strains. This permissiveness to L. pneumophila legS2 is neither attributed to abolished caspase-1, caspase-7 or caspase-3 activation, nor due to the impairment of phagosome-lysosome fusion. Instead, an infection with the legS2 mutant resulted in the reduction of some inflammatory cytokines and their corresponding mRNA; this effect is mediated by the inhibition of the nuclear transcription factor kappa-B (NF-κB). Moreover, BMDMs infected with L. pneumophila legS2 mutant showed elongated mitochondria that resembles mitochondrial fusion. Therefore, the absence of LegS2 effector is associated with reduced NF-κB activation and atypical morphology of mitochondria.
- Published
- 2016
- Full Text
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3. Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever
- Author
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Selina K. Jorch, Annika McNally, Philipp Berger, Jonas Wolf, Kim Kaiser, Andrian Chetrusca Covash, Stefanie Robeck, Isabell Pastau, Olesja Fehler, Saskia-L. Jauch-Speer, Sven Hermann, Michael Schäfers, Hanne Van Gorp, Apurva Kanneganti, Joke Dehoorne, Filomeen Haerynck, Federica Penco, Marco Gattorno, Jae Jin Chae, Paul Kubes, Mohamed Lamkanfi, Andy Wullaert, Markus Sperandio, Thomas Vogl, Johannes Roth, and Judith Austermann
- Subjects
Immunology ,Medicine and Health Sciences ,Biology and Life Sciences ,Immunology and Allergy - Published
- 2023
4. Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
- Author
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Hongbo Yu, Fei Liu, Hiroto Kambara, Xuemei Xie, Maikel Acosta-Zaldívar, Cunling Zhang, Julia R. Köhler, Jiajia Li, Hongbo R. Luo, Rongxia Guo, Ning-Ning Liu, Ting Bei, Fengxia Ma, Li Zhao, Xionghui Ding, Wenli Han, Xiaoyu Zhang, Wanjun Qi, and Apurva Kanneganti
- Subjects
Programmed cell death ,Inflammasomes ,Science ,Interleukin-1beta ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Kidney ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Sepsis ,Mediator ,Candida albicans ,medicine ,Animals ,Humans ,Cells, Cultured ,Mice, Knockout ,Multidisciplinary ,biology ,Immune cell death ,Macrophages ,Caspase 1 ,Candidiasis ,Intracellular Signaling Peptides and Proteins ,Pyroptosis ,Inflammasome ,General Chemistry ,Phosphate-Binding Proteins ,medicine.disease ,biology.organism_classification ,Corpus albicans ,Mice, Inbred C57BL ,Host-Pathogen Interactions ,Female ,Infection ,Candidalysin ,medicine.drug - Abstract
Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis., Inflammasome signalling has been shown to protect Candida albicans during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in C.ablicans immune evasion and suggests its targeting therapeutically.
- Published
- 2021
5. Inflammasome-Mediated GSDMD Activation Dictates Escape of Candida albicansfrom Macrophages
- Author
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Hiroto Kambara, Xionghui Ding, Apurva Kanneganti, Maikel Acosta-Zaldívar, Ting Bei, Wanjun Qi, Xuemei Xie, Wenli Han, Ningning Liu, Cunling Zhang, Xiaoyu Zhang, Hongbo Yu, Li Zhao, Yong Jiang, Fengxia Ma, Julia R. Köhler, and Hongbo Luo
- Published
- 2020
6. Homeostasis and transitional activation of regulatory T cells require c-Myc
- Author
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Geoffrey Neale, Yanyan Wang, Hongbo Chi, Peter Carmeliet, Daniel Bastardo Blanco, Peter Vogel, Apurva Kanneganti, Shaofeng Liu, Hu Zeng, Nicole M. Chapman, Yogesh Dhungana, Thanh-Long M. Nguyen, Jordy Saravia, and Jana L. Raynor
- Subjects
CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,T-Lymphocytes, Regulatory ,Oxidative Phosphorylation ,Mice ,0302 clinical medicine ,Transcriptional regulation ,Homeostasis ,Research Articles ,0303 health sciences ,Multidisciplinary ,Chemistry ,Effector ,digestive, oral, and skin physiology ,Fatty Acids ,SciAdv r-articles ,Life Sciences ,hemic and immune systems ,Flow Cytometry ,Cell biology ,Multidisciplinary Sciences ,medicine.anatomical_structure ,Science & Technology - Other Topics ,medicine.symptom ,Oxidation-Reduction ,Research Article ,EXPRESSION ,Regulatory T cell ,FOXP3 ,T cell ,Immunology ,Inflammation ,chemical and pharmacologic phenomena ,Oxidative phosphorylation ,METABOLISM ,IMMUNITY ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,INFLAMMATION ,medicine ,Animals ,030304 developmental biology ,Immunosuppression Therapy ,Alkyl and Aryl Transferases ,Science & Technology ,Carnitine O-Palmitoyltransferase ,STABILITY ,REPRESSION ,Membrane Proteins ,IMMUNOMETABOLISM ,MAINTENANCE ,Animals, Newborn ,IDENTITY ,CD8 ,030215 immunology - Abstract
c-Myc coordinates context-dependent homeostasis and transitional activation with metabolic programming of regulatory T cells., Regulatory T cell (Treg) activation and expansion occur during neonatal life and inflammation to establish immunosuppression, yet the mechanisms governing these events are incompletely understood. We report that the transcriptional regulator c-Myc (Myc) controls immune homeostasis through regulation of Treg accumulation and functional activation. Myc activity is enriched in Tregs generated during neonatal life and responding to inflammation. Myc-deficient Tregs show defects in accumulation and ability to transition to an activated state. Consequently, loss of Myc in Tregs results in an early-onset autoimmune disorder accompanied by uncontrolled effector CD4+ and CD8+ T cell responses. Mechanistically, Myc regulates mitochondrial oxidative metabolism but is dispensable for fatty acid oxidation (FAO). Indeed, Treg-specific deletion of Cox10, which promotes oxidative phosphorylation, but not Cpt1a, the rate-limiting enzyme for FAO, results in impaired Treg function and maturation. Thus, Myc coordinates Treg accumulation, transitional activation, and metabolic programming to orchestrate immune homeostasis.
- Published
- 2020
7. GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever
- Author
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Hanne Van Gorp, Apurva Kanneganti, Hiroto Kambara, Heather Tillman, R. K. Subbarao Malireddi, Lieselotte Vande Walle, Hongbo R. Luo, Mohamed Lamkanfi, Pedro Henrique Viana Saavedra, Hongbo Chi, Peter Vogel, and Ramnik J. Xavier
- Subjects
0301 basic medicine ,PYROPTOTIC CELL-DEATH ,Neutrophils ,Interleukin-1beta ,Familial Mediterranean fever ,Disease ,PYRIN INFLAMMASOME ACTIVATION ,Pyrin domain ,Mice ,0302 clinical medicine ,Medicine and Health Sciences ,Immunology and Allergy ,Research Articles ,Intracellular Signaling Peptides and Proteins ,Pyroptosis ,Inflammasome ,MEFV ,Familial Mediterranean Fever ,3. Good health ,DISEASES ,030220 oncology & carcinogenesis ,SECRETION ,Cytokines ,CASPASE-11 ,Inflammation Mediators ,medicine.symptom ,medicine.drug ,Immunology ,Caspase-11 ,03 medical and health sciences ,medicine ,Animals ,RELEASE ,Inflammation ,Clostridioides difficile ,Wasting Syndrome ,business.industry ,Macrophages ,Brief Definitive Report ,Biology and Life Sciences ,Phosphate-Binding Proteins ,Pyrin ,medicine.disease ,Neutrophilia ,GASDERMIN D ,Disease Models, Animal ,IL-1-BETA ,030104 developmental biology ,INTERLEUKIN-1-BETA ,Apoptosis Regulatory Proteins ,business ,Spleen - Abstract
Inflammasomes promote interleukin (IL)-1β secretion and pyroptosis. Kanneganti et al. now show that the pyroptosis effector gasdermin D (GSDMD) is required for systemic IL-1β secretion and autoinflammatory pathology in a mouse model of Familial Mediterranean Fever (FMF), suggesting GSDMD inhibitors as potential antiinflammatory treatments., Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated MefvV726A Pyrin elicited pyroptosis and gasdermin D (GSDMD)–mediated interleukin (IL)-1β secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1β–dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.
- Published
- 2018
8. Aging is associated with hypermethylation of autophagy genes in macrophages
- Author
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Apurva Kanneganti, Mia Tazi, Kyle Caution, Kaivon Assani, Duaa Dakhlallah, Amr E. Ahmed, Amal O. Amer, Clay B. Marsh, Hany Khalil, and Benjamin T. Kopp
- Subjects
0301 basic medicine ,Cancer Research ,Aging ,Methyltransferase ,ATG5 ,Inflammation ,Biology ,Catechin ,Autophagy-Related Protein 5 ,03 medical and health sciences ,Mice ,Gene expression ,medicine ,Autophagy ,Animals ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Enzyme Inhibitors ,RNA, Small Interfering ,Molecular Biology ,Gene ,Macrophages ,Autophagosomes ,Methylation ,DNA Methylation ,030104 developmental biology ,DNA methylation ,Cancer research ,medicine.symptom ,Microtubule-Associated Proteins ,Research Paper - Abstract
Autophagy is a biological process characterized by self-digestion and involves induction of autophagosome formation, leading to degradation of autophagic cargo. Aging is associated with the reduction of autophagy activity leading to neurodegenerative disorders, chronic inflammation, and susceptibility to infection; however, the underlying mechanism is unclear. DNA methylation by DNA methyltransferases reduces the expression of corresponding genes. Since macrophages are major players in inflammation and defense against infection we determined the differences in methylation of autophagy genes in macrophages derived from young and aged mice. We found that promoter regions of Atg5 and LC3B are hypermethylated in macrophages from aged mice and this is accompanied by low gene expression. Treatment of aged mice and their derived macrophages with methyltransferase inhibitor (2)-epigallocatechin-3-gallate (EGCG) or specific DNA methyltransferase 2 (DNMT2) siRNA restored the expression of Atg5 and LC3 in vivo and in vitro. Our study builds a foundation for the development of novel therapeutics aimed to improve autophagy in the elderly population and suggests a role for DNMT2 in DNA methylation activities.
- Published
- 2017
9. Caspase-11 and caspase-1 differentially modulate actin polymerization via RhoA and Slingshot proteins to promote bacterial clearance
- Author
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Kyle Caution, Mikhail A. Gavrilin, Daniel Layman, Mia Tazi, Kathrin Krause, Amal O. Amer, Sheshadri Hoque, and Apurva Kanneganti
- Subjects
Cofilin 1 ,0301 basic medicine ,RHOA ,Inflammasomes ,Vesicular Transport Proteins ,Receptors, Cell Surface ,macromolecular substances ,Caspase-11 ,Vacuole ,Article ,Legionella pneumophila ,Mice ,03 medical and health sciences ,Phosphoprotein Phosphatases ,medicine ,Animals ,Humans ,Actin ,Mice, Knockout ,Multidisciplinary ,Slingshot ,biology ,Caspase 1 ,Inflammasome ,Cofilin ,Actins ,Cell biology ,030104 developmental biology ,Multiprotein Complexes ,Vacuoles ,biology.protein ,Legionnaires' Disease ,Lysosomes ,rhoA GTP-Binding Protein ,medicine.drug - Abstract
Inflammasomes are multiprotein complexes that include members of the NOD-like receptor family and caspase-1. Caspase-1 is required for the fusion of the Legionella vacuole with lysosomes. Caspase-11, independently of the inflammasome, also promotes phagolysosomal fusion. However, it is unclear how these proteases alter intracellular trafficking. Here, we show that caspase-11 and caspase-1 function in opposing manners to phosphorylate and dephosphorylate cofilin, respectively upon infection with Legionella. Caspase-11 targets cofilin via the RhoA GTPase, whereas caspase-1 engages the Slingshot phosphatase. The absence of either caspase-11 or caspase-1 maintains actin in the polymerized or depolymerized form, respectively and averts the fusion of pathogen-containing vacuoles with lysosomes. Therefore, caspase-11 and caspase-1 converge on the actin machinery with opposing effects to promote vesicular trafficking.
- Published
- 2015
10. The Sphingosine-1-Phosphate Lyase (LegS2) Contributes to the Restriction of Legionella pneumophila in Murine Macrophages
- Author
-
Amal O. Amer, Arwa Abu Khweek, Denis C. Guttridge D, and Apurva Kanneganti
- Subjects
0301 basic medicine ,Mutant ,lcsh:Medicine ,Membrane Fusion ,Legionella pneumophila ,Mice ,chemistry.chemical_compound ,Mice, Inbred NOD ,Sphingosine ,Phagosomes ,lcsh:Science ,Bacterial Secretion Systems ,Disease Resistance ,Caspase 7 ,Multidisciplinary ,Caspase 3 ,Effector ,Caspase 1 ,NF-kappa B ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Legionnaires' Disease ,Research Article ,Signal Transduction ,030106 microbiology ,Biology ,Microbiology ,03 medical and health sciences ,Species Specificity ,Lysosome ,medicine ,Animals ,Humans ,Secretion ,Aldehyde-Lyases ,Macrophages ,Calcium-Binding Proteins ,lcsh:R ,biology.organism_classification ,Lyase ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,lcsh:Q ,Lysophospholipids ,Apoptosis Regulatory Proteins ,Lysosomes - Abstract
L. pneumophila is the causative agent of Legionnaires' disease, a human illness characterized by severe pneumonia. In contrast to those derived from humans, macrophages derived from most mouse strains restrict L. pneumophila replication. The restriction of L. pneumophila replication has been shown to require bacterial flagellin, a component of the type IV secretion system as well as the cytosolic NOD-like receptor (NLR) Nlrc4/ Ipaf. These events lead to caspase-1 activation which, in turn, activates caspase-7. Following caspase-7 activation, the phagosome-containing L. pneumophila fuses with the lysosome, resulting in the restriction of L. pneumophila growth. The LegS2 effector is injected by the type IV secretion system and functions as a sphingosine 1-phosphate lyase. It is homologous to the eukaryotic sphingosine lyase (SPL), an enzyme required in the terminal steps of sphingolipid metabolism. Herein, we show that mice Bone Marrow-Derived Macrophages (BMDMs) and human Monocyte-Derived Macrophages (hMDMs) are more permissive to L. pneumophila legS2 mutants than wild-type (WT) strains. This permissiveness to L. pneumophila legS2 is neither attributed to abolished caspase-1, caspase-7 or caspase-3 activation, nor due to the impairment of phagosome-lysosome fusion. Instead, an infection with the legS2 mutant resulted in the reduction of some inflammatory cytokines and their corresponding mRNA; this effect is mediated by the inhibition of the nuclear transcription factor kappa-B (NF-κB). Moreover, BMDMs infected with L. pneumophila legS2 mutant showed elongated mitochondria that resembles mitochondrial fusion. Therefore, the absence of LegS2 effector is associated with reduced NF-κB activation and atypical morphology of mitochondria.
- Published
- 2016
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