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Jean-laurent Casanova - One of the best experts on this subject based on the ideXlab platform.
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Deficiency of Interleukin-1 Receptor-Associated Kinase 4 presenting as fatal Pseudomonas aeruginosa bacteremia in two siblings.
The Pediatric infectious disease journal, 2015Co-Authors: Theodouli Stergiopoulou, Jean-laurent Casanova, Thomas J. Walsh, Marie Christine Seghaye, Mihai G. Netea, Michel Moutschen, Capucine PicardAbstract:Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency is a primary immunodeficiency of innate immunity. This is the case of a previous healthy toddler and his sibling, who both died of fulminant sepsis due to Pseudomonas aeruginosa. Subsequent genetic analysis demonstrated IRAK-4 deficiency with compound heterozygous splice mutations. Fulminant fatal P. aeruginosa sepsis may be the first manifestation of IRAK-4 deficiency.
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very late onset group b streptococcus meningitis sepsis and systemic shigellosis due to interleukin 1 receptor associated Kinase 4 deficiency
Clinical Infectious Diseases, 2009Co-Authors: Jens C Krause, Capucine Picard, Jean-laurent Casanova, Pegah Ghandil, Maya Chrabieh, Anne PuelAbstract:We describe a child with very late-onset group B Streptococcus sepsis and meningitis, systemic shigellosis, and chronic osteomyelitis. Peripheral blood cells obtained from the patient and her brother did not respond to stimulation with either Interleukin-1β or lipopolysaccharide. Sequencing of the Interleukin-1 Receptor-Associated Kinase-4 gene revealed 2 novel mutations.
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Autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 deficiency in fourth-degree relatives
The Journal of pediatrics, 2006Co-Authors: María Cárdenes, Horst Von Bernuth, Ayoze Garcia-saavedra, Esther Santiago, Anne Puel, Jean-françois Emile, Capucine Picard, Jean-laurent Casanova, Elena ColinoAbstract:We report a kindred with autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency in 3 fourth-degree relatives. A diagnosis of IRAK-4 deficiency should be considered in families with invasive bacterial disease, even if the individuals affected are only distantly related, which falsely suggests multigenic or dominant inheritance with low penetrance.
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shigella sonnei meningitis due to interleukin 1 receptor associated Kinase 4 deficiency first association with a primary immune deficiency
Clinical Infectious Diseases, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
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Shigella sonnei Meningitis Due to Interleukin-1 Receptor—Associated Kinase—4 Deficiency: First Association with a Primary Immune Deficiency
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
Capucine Picard - One of the best experts on this subject based on the ideXlab platform.
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Deficiency of Interleukin-1 Receptor-Associated Kinase 4 presenting as fatal Pseudomonas aeruginosa bacteremia in two siblings.
The Pediatric infectious disease journal, 2015Co-Authors: Theodouli Stergiopoulou, Jean-laurent Casanova, Thomas J. Walsh, Marie Christine Seghaye, Mihai G. Netea, Michel Moutschen, Capucine PicardAbstract:Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency is a primary immunodeficiency of innate immunity. This is the case of a previous healthy toddler and his sibling, who both died of fulminant sepsis due to Pseudomonas aeruginosa. Subsequent genetic analysis demonstrated IRAK-4 deficiency with compound heterozygous splice mutations. Fulminant fatal P. aeruginosa sepsis may be the first manifestation of IRAK-4 deficiency.
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very late onset group b streptococcus meningitis sepsis and systemic shigellosis due to interleukin 1 receptor associated Kinase 4 deficiency
Clinical Infectious Diseases, 2009Co-Authors: Jens C Krause, Capucine Picard, Jean-laurent Casanova, Pegah Ghandil, Maya Chrabieh, Anne PuelAbstract:We describe a child with very late-onset group B Streptococcus sepsis and meningitis, systemic shigellosis, and chronic osteomyelitis. Peripheral blood cells obtained from the patient and her brother did not respond to stimulation with either Interleukin-1β or lipopolysaccharide. Sequencing of the Interleukin-1 Receptor-Associated Kinase-4 gene revealed 2 novel mutations.
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Autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 deficiency in fourth-degree relatives
The Journal of pediatrics, 2006Co-Authors: María Cárdenes, Horst Von Bernuth, Ayoze Garcia-saavedra, Esther Santiago, Anne Puel, Jean-françois Emile, Capucine Picard, Jean-laurent Casanova, Elena ColinoAbstract:We report a kindred with autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency in 3 fourth-degree relatives. A diagnosis of IRAK-4 deficiency should be considered in families with invasive bacterial disease, even if the individuals affected are only distantly related, which falsely suggests multigenic or dominant inheritance with low penetrance.
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shigella sonnei meningitis due to interleukin 1 receptor associated Kinase 4 deficiency first association with a primary immune deficiency
Clinical Infectious Diseases, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
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Shigella sonnei Meningitis Due to Interleukin-1 Receptor—Associated Kinase—4 Deficiency: First Association with a Primary Immune Deficiency
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
Anne Puel - One of the best experts on this subject based on the ideXlab platform.
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very late onset group b streptococcus meningitis sepsis and systemic shigellosis due to interleukin 1 receptor associated Kinase 4 deficiency
Clinical Infectious Diseases, 2009Co-Authors: Jens C Krause, Capucine Picard, Jean-laurent Casanova, Pegah Ghandil, Maya Chrabieh, Anne PuelAbstract:We describe a child with very late-onset group B Streptococcus sepsis and meningitis, systemic shigellosis, and chronic osteomyelitis. Peripheral blood cells obtained from the patient and her brother did not respond to stimulation with either Interleukin-1β or lipopolysaccharide. Sequencing of the Interleukin-1 Receptor-Associated Kinase-4 gene revealed 2 novel mutations.
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Autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 deficiency in fourth-degree relatives
The Journal of pediatrics, 2006Co-Authors: María Cárdenes, Horst Von Bernuth, Ayoze Garcia-saavedra, Esther Santiago, Anne Puel, Jean-françois Emile, Capucine Picard, Jean-laurent Casanova, Elena ColinoAbstract:We report a kindred with autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency in 3 fourth-degree relatives. A diagnosis of IRAK-4 deficiency should be considered in families with invasive bacterial disease, even if the individuals affected are only distantly related, which falsely suggests multigenic or dominant inheritance with low penetrance.
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shigella sonnei meningitis due to interleukin 1 receptor associated Kinase 4 deficiency first association with a primary immune deficiency
Clinical Infectious Diseases, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
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Shigella sonnei Meningitis Due to Interleukin-1 Receptor—Associated Kinase—4 Deficiency: First Association with a Primary Immune Deficiency
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
Horst Von Bernuth - One of the best experts on this subject based on the ideXlab platform.
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Liver abscess complicated by diaphragm perforation and pleural empyema leads to the discovery of Interleukin-1 Receptor-Associated Kinase 4 deficiency.
The Pediatric infectious disease journal, 2014Co-Authors: Dominik Schöndorf, Horst Von Bernuth, Arne Simon, Günther Schneider, Uwe Kölsch, Klaus Schwarz, Clemens-magnus Meier, Jörg Groe-onnebrink, Ludwig Gortner, Tilman R RohrerAbstract:Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency predisposes to severe invasive bacterial infections in infancy and early childhood, often with a fatal course caused by a defect in Toll-like receptor and Interleukin-1 receptor signaling. Despite severe invasive infections, acute phase responses are often diminished. We report the successful treatment of a child with multiple liver abscesses, diaphragm perforation and pleural empyema, accompanied by strong acute phase responses as a unique presentation of IRAK-4 deficiency.
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Even in pneumococcal sepsis CD62L shedding on granulocytes proves to be a reliable functional test for the diagnosis of Interleukin-1 Receptor-Associated Kinase-4 deficiency.
The Pediatric infectious disease journal, 2013Co-Authors: Oliver Andres, Horst Von Bernuth, Uwe Kölsch, Klaus Schwarz, Karoline Strehl, Steffen Kunzmann, Anne-hélène Lebrun, Thorsten Stroh, Henner Morbach, Johannes LiefseAbstract:A 9-month-old infant presented with fatal pneumococcal sepsis and attenuated inflammation indices. Even in septic conditions, flow cytometry-based CD62L shedding test on granulocytes proved to be a fast and reliable diagnostic tool for the detection of a defect in the innate immunity. Confirmatory immunologic and genetic assays identified an autosomal-recessive Interleukin-1 Receptor-Associated Kinase-4 deficiency due to compound heterozygous mutations.
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Autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 deficiency in fourth-degree relatives
The Journal of pediatrics, 2006Co-Authors: María Cárdenes, Horst Von Bernuth, Ayoze Garcia-saavedra, Esther Santiago, Anne Puel, Jean-françois Emile, Capucine Picard, Jean-laurent Casanova, Elena ColinoAbstract:We report a kindred with autosomal recessive Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) deficiency in 3 fourth-degree relatives. A diagnosis of IRAK-4 deficiency should be considered in families with invasive bacterial disease, even if the individuals affected are only distantly related, which falsely suggests multigenic or dominant inheritance with low penetrance.
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shigella sonnei meningitis due to interleukin 1 receptor associated Kinase 4 deficiency first association with a primary immune deficiency
Clinical Infectious Diseases, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
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Shigella sonnei Meningitis Due to Interleukin-1 Receptor—Associated Kinase—4 Deficiency: First Association with a Primary Immune Deficiency
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005Co-Authors: Helen Chapel, Horst Von Bernuth, Anne Puel, Capucine Picard, Jean-laurent CasanovaAbstract:BACKGROUND: Inherited Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.
Yasuko Matsuzawa - One of the best experts on this subject based on the ideXlab platform.
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Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) Is a Critical Mediator of Endoplasmic Reticulum (ER) Stress Signaling
PloS one, 2013Co-Authors: Samir Benosman, James A. Thomas, Ying-chen Hou, Ricardo G. Correa, Muhammet F. Gulen, Palaniyandi Ravanan, Michael Cuddy, Yasuko MatsuzawaAbstract:Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress Kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress Kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway.
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Abstract 2928: Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress.
Molecular and Cellular Biology, 2013Co-Authors: Ravanan Palaniyandi, Samir Benosman, Ying-chen Hou, Ricardo G. Correa, Muhammet F. Gulen, James Thomas, Yasuko Matsuzawa, Shu-ichi MatsuzawaAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases, including cancer where harsh tumor microenvironments induce ER stress and create pressure for evolution of malignant clones that have acquired mechanisms for successful adaptation to stressful environments. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress Kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress Kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway involved in ER stress signaling. Future analysis of the role of IRAK2 in animal models of cancer will aid in assessing whether IRAK2 provides a novel targets for potential cancer therapeutics development. (Supported by NIH grant AG-15393). Citation Format: Ravanan Palaniyandi, Samir Benosman, Ying-Chen Hou, Ricardo G. Correa, Minjia Yu, Muhammet Fatih Gulen, Xiaoxia Li, James Thomas, Yasuko Matsuzawa, Shu-Ichi Matsuzawa, John C. Reed. Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2928. doi:10.1158/1538-7445.AM2013-2928 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.