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  1. Article ; Online: Microbes mediate mitochondrial misinformation to misguide neutrophils.

    Karmakar, Mausita / Dubyak, George R

    Journal of leukocyte biology

    2019  Volume 106, Issue 6, Page(s) 1197–1200

    Abstract: Discussion on LPS disruption of mitochondrial localization and autocrine purinergic signaling in neutrophil chemotaxis for control of E. coli infection. ...

    Abstract Discussion on LPS disruption of mitochondrial localization and autocrine purinergic signaling in neutrophil chemotaxis for control of E. coli infection.
    MeSH term(s) Anti-Infective Agents ; Chemotaxis ; Communication ; Escherichia coli ; Lipopolysaccharides ; Neutrophils
    Chemical Substances Anti-Infective Agents ; Lipopolysaccharides
    Language English
    Publishing date 2019-10-21
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.3CE0819-263
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  2. Article ; Online: Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP

    Mausita Karmakar / Michael A. Katsnelson / George R. Dubyak / Eric Pearlman

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 13

    Abstract: Neutrophils are a major source of IL-1 β in a number of inflammatory settings. Here the authors show that mouse and human neutrophils express functional P2X7 receptors, which mediate ATP-triggered NLRP3 inflammasome activation and IL-1 ß secretion. ...

    Abstract Neutrophils are a major source of IL-1 β in a number of inflammatory settings. Here the authors show that mouse and human neutrophils express functional P2X7 receptors, which mediate ATP-triggered NLRP3 inflammasome activation and IL-1 ß secretion.
    Keywords Science ; Q
    Language English
    Publishing date 2016-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
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  3. Article ; Online: Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP.

    Karmakar, Mausita / Katsnelson, Michael A / Dubyak, George R / Pearlman, Eric

    Nature communications

    2016  Volume 7, Page(s) 10555

    Abstract: Although extracellular ATP is abundant at sites of inflammation, its role in activating inflammasome signalling in neutrophils is not well characterized. In the current study, we demonstrate that human and murine neutrophils express functional cell- ... ...

    Abstract Although extracellular ATP is abundant at sites of inflammation, its role in activating inflammasome signalling in neutrophils is not well characterized. In the current study, we demonstrate that human and murine neutrophils express functional cell-surface P2X7R, which leads to ATP-induced loss of intracellular K(+), NLRP3 inflammasome activation and IL-1β secretion. ATP-induced P2X7R activation caused a sustained increase in intracellular [Ca(2+)], which is indicative of P2X7R channel opening. Although there are multiple polymorphic variants of P2X7R, we found that neutrophils from multiple donors express P2X7R, but with differential efficacies in ATP-induced increase in cytosolic [Ca(2+)]. Neutrophils were also the predominant P2X7R-expressing cells during Streptococcus pneumoniae corneal infection, and P2X7R was required for bacterial clearance. Given the ubiquitous presence of neutrophils and extracellular ATP in multiple inflammatory conditions, ATP-induced P2X7R activation and IL-1β secretion by neutrophils likely has a significant, wide ranging clinical impact.
    MeSH term(s) Adenosine Triphosphate/immunology ; Animals ; Blotting, Western ; Calcium/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Eye Infections, Bacterial/immunology ; Flow Cytometry ; Humans ; Inflammasomes/immunology ; Interleukin-1beta/secretion ; Keratitis/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Fluorescence ; NLR Family, Pyrin Domain-Containing 3 Protein ; Neutrophils/drug effects ; Neutrophils/immunology ; Neutrophils/metabolism ; Potassium/metabolism ; Purinergic P2X Receptor Antagonists/pharmacology ; Receptors, Purinergic P2X7/immunology ; Spectrophotometry, Atomic ; Streptococcal Infections/immunology
    Chemical Substances Carrier Proteins ; IL1B protein, human ; IL1B protein, mouse ; Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; Nlrp3 protein, mouse ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7 ; Adenosine Triphosphate (8L70Q75FXE) ; Potassium (RWP5GA015D) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2016-02-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2041-1723
    ISSN (online) 2041-1723
    DOI 10.1038/ncomms10555
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  4. Article ; Online: Neutrophil Caspase-11 Is Required for Cleavage of Caspase-1 and Secretion of IL-1β in

    Sun, Yan / Abbondante, Serena / Karmakar, Mausita / de Jesus Carrion, Steven / Che, Chengye / Hise, Amy G / Pearlman, Eric

    Journal of immunology (Baltimore, Md. : 1950)

    2018  Volume 201, Issue 9, Page(s) 2767–2775

    Abstract: Neutrophils are an important source of IL-1β secretion in bacterial infections, where they infiltrate affected tissues in log-fold higher numbers than macrophages. Neutrophils also have functional NLRP3 and NLRC4 inflammasomes that can process pro-IL-1β ... ...

    Abstract Neutrophils are an important source of IL-1β secretion in bacterial infections, where they infiltrate affected tissues in log-fold higher numbers than macrophages. Neutrophils also have functional NLRP3 and NLRC4 inflammasomes that can process pro-IL-1β to the bioactive 17-kDa form. In the current study, we examined the role of IL-1β in response to corneal infection with the filamentous fungus
    MeSH term(s) Animals ; Aspergillosis/immunology ; Aspergillus fumigatus/immunology ; Caspase 1/metabolism ; Caspases/metabolism ; Interleukin-1beta/biosynthesis ; Keratitis/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils/immunology ; Neutrophils/metabolism ; Signal Transduction/immunology
    Chemical Substances Interleukin-1beta ; Casp11 protein, mouse (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Casp1 protein, mouse (EC 3.4.22.36) ; Caspase 1 (EC 3.4.22.36)
    Language English
    Publishing date 2018-09-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1701195
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  5. Article ; Online: Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils.

    Vareechon, Chairut / Zmina, Stephanie Elizabeth / Karmakar, Mausita / Pearlman, Eric / Rietsch, Arne

    Cell host & microbe

    2017  Volume 21, Issue 5, Page(s) 611–618.e5

    Abstract: Neutrophils are the first line of defense against bacterial infections, and the generation of reactive oxygen species is a key part of their arsenal. Pathogens use detoxification systems to avoid the bactericidal effects of reactive oxygen species. Here ... ...

    Abstract Neutrophils are the first line of defense against bacterial infections, and the generation of reactive oxygen species is a key part of their arsenal. Pathogens use detoxification systems to avoid the bactericidal effects of reactive oxygen species. Here we demonstrate that the Gram-negative pathogen Pseudomonas aeruginosa is susceptible to reactive oxygen species but actively blocks the reactive oxygen species burst using two type III secreted effector proteins, ExoS and ExoT. ExoS ADP-ribosylates Ras and prevents it from interacting with and activating phosphoinositol-3-kinase (PI3K), which is required to stimulate the phagocytic NADPH-oxidase that generates reactive oxygen species. ExoT also affects PI3K signaling via its ADP-ribosyltransferase activity but does not act directly on Ras. A non-ribosylatable version of Ras restores reactive oxygen species production and results in increased bacterial killing. These findings demonstrate that subversion of the host innate immune response requires ExoS-mediated ADP-ribosylation of Ras in neutrophils.
    MeSH term(s) ADP Ribose Transferases/antagonists & inhibitors ; ADP Ribose Transferases/metabolism ; ADP-Ribosylation/drug effects ; Animals ; Bacterial Toxins/antagonists & inhibitors ; Bacterial Toxins/immunology ; Colony Count, Microbial ; Epithelium/pathology ; Eye/pathology ; Female ; GTPase-Activating Proteins/antagonists & inhibitors ; Humans ; Immunity, Innate ; Mice, Inbred C57BL ; NADPH Oxidases/metabolism ; Neutrophils/enzymology ; Neutrophils/immunology ; Neutrophils/metabolism ; Phagocytosis ; Phosphatidylinositol 3-Kinases/metabolism ; Pseudomonas Infections/immunology ; Pseudomonas Infections/microbiology ; Pseudomonas aeruginosa/immunology ; Pseudomonas aeruginosa/metabolism ; Pseudomonas aeruginosa/pathogenicity ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Survival Analysis ; Type III Secretion Systems/drug effects ; ras Proteins/drug effects ; ras Proteins/metabolism
    Chemical Substances Bacterial Toxins ; ExoT protein, Pseudomonas aeruginosa ; GTPase-Activating Proteins ; Reactive Oxygen Species ; Type III Secretion Systems ; NADPH Oxidases (EC 1.6.3.-) ; ADP Ribose Transferases (EC 2.4.2.-) ; exoenzyme S (EC 2.4.2.31) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2017-05-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2278004-X
    ISSN 1934-6069 ; 1931-3128
    ISSN (online) 1934-6069
    ISSN 1931-3128
    DOI 10.1016/j.chom.2017.04.001
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  6. Article ; Online: N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis.

    Karmakar, Mausita / Minns, Martin / Greenberg, Elyse N / Diaz-Aponte, Jose / Pestonjamasp, Kersi / Johnson, Jennifer L / Rathkey, Joseph K / Abbott, Derek W / Wang, Kun / Shao, Feng / Catz, Sergio D / Dubyak, George R / Pearlman, Eric

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 2212

    Abstract: Gasdermin-D (GSDMD) in inflammasome-activated macrophages is cleaved by caspase-1 to generate N-GSDMD fragments. N-GSDMD then oligomerizes in the plasma membrane (PM) to form pores that increase membrane permeability, leading to pyroptosis and IL-1β ... ...

    Abstract Gasdermin-D (GSDMD) in inflammasome-activated macrophages is cleaved by caspase-1 to generate N-GSDMD fragments. N-GSDMD then oligomerizes in the plasma membrane (PM) to form pores that increase membrane permeability, leading to pyroptosis and IL-1β release. In contrast, we report that although N-GSDMD is required for IL-1β secretion in NLRP3-activated human and murine neutrophils, N-GSDMD does not localize to the PM or increase PM permeability or pyroptosis. Instead, biochemical and microscopy studies reveal that N-GSDMD in neutrophils predominantly associates with azurophilic granules and LC3
    MeSH term(s) Animals ; Autophagosomes/metabolism ; Autophagy/genetics ; Caspase 1/metabolism ; Cell Membrane/metabolism ; Cell Membrane Permeability/genetics ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Leukocyte Elastase/genetics ; Leukocyte Elastase/metabolism ; Macrophages/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils/metabolism ; Organelles/metabolism ; Phosphate-Binding Proteins/genetics ; Phosphate-Binding Proteins/metabolism ; Protein Transport ; Pyroptosis/genetics
    Chemical Substances GSDMD protein, human ; IL1B protein, human ; Inflammasomes ; Interleukin-1beta ; Intracellular Signaling Peptides and Proteins ; Phosphate-Binding Proteins ; Leukocyte Elastase (EC 3.4.21.37) ; Caspase 1 (EC 3.4.22.36)
    Language English
    Publishing date 2020-05-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-16043-9
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  7. Article ; Online: CD14 mediates Toll-like receptor 4 (TLR4) endocytosis and spleen tyrosine kinase (Syk) and interferon regulatory transcription factor 3 (IRF3) activation in epithelial cells and impairs neutrophil infiltration and Pseudomonas aeruginosa killing in vivo.

    Roy, Sanhita / Karmakar, Mausita / Pearlman, Eric

    The Journal of biological chemistry

    2013  Volume 289, Issue 2, Page(s) 1174–1182

    Abstract: In the current study, we examined the role of CD14 in regulating LPS activation of corneal epithelial cells and Pseudomonas aeruginosa corneal infection. Our findings demonstrate that LPS induces Toll-like receptor 4 (TLR4) internalization in corneal ... ...

    Abstract In the current study, we examined the role of CD14 in regulating LPS activation of corneal epithelial cells and Pseudomonas aeruginosa corneal infection. Our findings demonstrate that LPS induces Toll-like receptor 4 (TLR4) internalization in corneal epithelial cells and that blocking with anti-CD14 selectively inhibits TLR4 endocytosis, spleen tyrosine kinase (Syk) and IRF3 phosphorylation, and production of CCL5/RANTES and IFN-β, but not IL-8. Using a murine model of P. aeruginosa corneal infection, we show that although infected CD14(-/-) corneas produce less CCL5, they exhibit significantly increased CXC chemokine production, neutrophil recruitment to the corneal stroma, and bacterial clearance than C57BL/6 mice. We conclude that CD14 has a critical role in mediating TLR4 signaling through IRF3 in resident corneal epithelial cells and macrophages and thereby modulates TLR4 cell surface activation of the MyD88/NF-κB/AP-1 pathway and production of CXC chemokines and neutrophil infiltration to infected tissues.
    MeSH term(s) Animals ; Blotting, Western ; Cell Line ; Cells, Cultured ; Chemokine CCL5/immunology ; Chemokine CCL5/metabolism ; Cornea/cytology ; Cornea/immunology ; Cornea/microbiology ; Endocytosis/drug effects ; Endocytosis/immunology ; Epithelial Cells/immunology ; Epithelial Cells/metabolism ; Epithelial Cells/microbiology ; Host-Pathogen Interactions/immunology ; Humans ; Interferon Regulatory Factor-3/immunology ; Interferon Regulatory Factor-3/metabolism ; Interferon-beta/immunology ; Interferon-beta/metabolism ; Intracellular Signaling Peptides and Proteins/immunology ; Intracellular Signaling Peptides and Proteins/metabolism ; Lipopolysaccharide Receptors/genetics ; Lipopolysaccharide Receptors/immunology ; Lipopolysaccharide Receptors/metabolism ; Lipopolysaccharides/immunology ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophil Infiltration/drug effects ; Neutrophil Infiltration/immunology ; Phosphorylation/drug effects ; Phosphorylation/immunology ; Protein-Tyrosine Kinases/immunology ; Protein-Tyrosine Kinases/metabolism ; Pseudomonas Infections/immunology ; Pseudomonas Infections/microbiology ; Pseudomonas aeruginosa/immunology ; Pseudomonas aeruginosa/physiology ; Syk Kinase ; Toll-Like Receptor 4/immunology ; Toll-Like Receptor 4/metabolism
    Chemical Substances Chemokine CCL5 ; Interferon Regulatory Factor-3 ; Intracellular Signaling Peptides and Proteins ; Lipopolysaccharide Receptors ; Lipopolysaccharides ; Toll-Like Receptor 4 ; Interferon-beta (77238-31-4) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; SYK protein, human (EC 2.7.10.2) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2)
    Language English
    Publishing date 2013-11-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M113.523167
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  8. Article ; Online: N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis

    Mausita Karmakar / Martin Minns / Elyse N. Greenberg / Jose Diaz-Aponte / Kersi Pestonjamasp / Jennifer L. Johnson / Joseph K. Rathkey / Derek W. Abbott / Kun Wang / Feng Shao / Sergio D. Catz / George R. Dubyak / Eric Pearlman

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic ... ...

    Abstract In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
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  9. Article ; Online: N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis

    Mausita Karmakar / Martin Minns / Elyse N. Greenberg / Jose Diaz-Aponte / Kersi Pestonjamasp / Jennifer L. Johnson / Joseph K. Rathkey / Derek W. Abbott / Kun Wang / Feng Shao / Sergio D. Catz / George R. Dubyak / Eric Pearlman

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic ... ...

    Abstract In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
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  10. Article ; Online: ExoS and ExoT ADP ribosyltransferase activities mediate Pseudomonas aeruginosa keratitis by promoting neutrophil apoptosis and bacterial survival.

    Sun, Yan / Karmakar, Mausita / Taylor, Patricia R / Rietsch, Arne / Pearlman, Eric

    Journal of immunology (Baltimore, Md. : 1950)

    2012  Volume 188, Issue 4, Page(s) 1884–1895

    Abstract: Pseudomonas aeruginosa is a leading cause of blinding corneal ulcers worldwide. To determine the role of type III secretion in the pathogenesis of P. aeruginosa keratitis, corneas of C57BL/6 mice were infected with P. aeruginosa strain PAO1 or PAK, which ...

    Abstract Pseudomonas aeruginosa is a leading cause of blinding corneal ulcers worldwide. To determine the role of type III secretion in the pathogenesis of P. aeruginosa keratitis, corneas of C57BL/6 mice were infected with P. aeruginosa strain PAO1 or PAK, which expresses ExoS, ExoT, and ExoY, but not ExoU. PAO1- and PAK-infected corneas developed severe disease with pronounced opacification and rapid bacterial growth. In contrast, corneas infected with ΔpscD or ΔpscJ mutants that cannot assemble a type III secretion system, or with mutants lacking the translocator proteins, do not develop clinical disease, and bacteria are rapidly killed by infiltrating neutrophils. Furthermore, survival of PAO1 and PAK strains in the cornea and development of corneal disease was impaired in ΔexoS, ΔexoT, and ΔexoST mutants of both strains, but not in a ΔexoY mutant. ΔexoST mutants were also rapidly killed in neutrophils in vitro and were impaired in their ability to promote neutrophil apoptosis in vivo compared with PAO1. Point mutations in the ADP ribosyltransferase (ADPR) regions of ExoS or ExoT also impaired proapoptotic activity in infected neutrophils, and exoST(ADPR-) mutants replicated the ΔexoST phenotype in vitro and in vivo, whereas mutations in rho-GTPase-activating protein showed the same phenotype as PAO1. Together, these findings demonstrate that the pathogenesis of P. aeruginosa keratitis in ExoS- and ExoT-producing strains is almost entirely due to their ADPR activities, which subvert the host response by targeting the antibacterial activity of infiltrating neutrophils.
    MeSH term(s) ADP Ribose Transferases/genetics ; ADP Ribose Transferases/metabolism ; Animals ; Apoptosis ; Bacterial Proteins/biosynthesis ; Bacterial Secretion Systems/genetics ; Bacterial Toxins/genetics ; Bacterial Toxins/metabolism ; Cells, Cultured ; Cornea/immunology ; Cornea/microbiology ; Cornea/pathology ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Glucosyltransferases/biosynthesis ; Keratitis/microbiology ; Keratitis/pathology ; Mice ; Mice, Inbred C57BL ; Neutrophils/physiology ; Pseudomonas aeruginosa/genetics ; Pseudomonas aeruginosa/growth & development ; Pseudomonas aeruginosa/metabolism ; Pseudomonas aeruginosa/pathogenicity
    Chemical Substances Bacterial Proteins ; Bacterial Secretion Systems ; Bacterial Toxins ; ExoT protein, Pseudomonas aeruginosa ; GTPase-Activating Proteins ; pseudomonas exoprotein A protein, Pseudomonas aeruginosa ; ExoY protein, bacteria (EC 2.4.-) ; Glucosyltransferases (EC 2.4.1.-) ; ADP Ribose Transferases (EC 2.4.2.-) ; exoenzyme S (EC 2.4.2.31)
    Language English
    Publishing date 2012-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1102148
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