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Theodore J. Standiford - One of the best experts on this subject based on the ideXlab platform.
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redundant and cooperative interactions between tlr5 and nlrc4 in protective lung Mucosal Immunity against pseudomonas aeruginosa
Journal of Innate Immunity, 2014Co-Authors: Fushin X Yu, Melissa A Kovach, Xianying Zeng, Leslie B Tolle, Megan N Ballinger, Michael W. Newstead, Gabriel Nunez, Theodore J. StandifordAbstract:Flagellin is the major structural component of flagella expressed by Pseudomonas aeruginosa (PA) and other bacteria. This protein has been shown to activate the Toll-like receptor TLR5 and the Nod-like receptor Nlrc4/Ipaf, culminating in the expression of innate cytokines and antimicrobial molecules. In this study, we tested the hypothesis that TLR5 and Nlrc4 in combination are required for maximal protective lung innate Mucosal Immunity against PA. To test this hypothesis, we compared innate immune responses in wild-type (WT) C57B6 mice challenged with PA intratracheally to those observed in mice genetically deficient in TLR5 (TLR5-/-) or Nlrc4 (Nlrc4-/-) alone or in combination (TLR5/Nlrc4-/-). As compared to WT, TLR5-/- and Nlrc4-/- mice, we observed a significant increase in mortality in TLR5/Nlrc4-/- mice, which was associated with a >5,000-fold increase in lung PA colony-forming units and systemic bacterial dissemination. The increased mortality observed in double-deficient mice was not attributable to differences in lung leukocyte influx or lung injury responses. Levels of biologically active IL-1β and IL-18 were reduced in the bronchoalveolar lavage fluid from PA-infected Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, indicating the requirement for Nlrc4-dependent caspase-1 activation. Similarly, decreased production of biologically active IL-1β and activation of caspase-1 was observed in PA-stimulated pulmonary macrophages isolated from Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, whereas the expression of iNOS and the production of NO were significantly reduced in cells from double-mutant but not single-mutant mice. Collectively, our findings indicate that TLR5 and Nlrc4 have both unique and redundant roles in lung antibacterial Mucosal Immunity, and the absence of both pathogen recognition receptors results in an increase in susceptibility to invasive lung infection.
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cathelicidin related antimicrobial peptide is required for effective lung Mucosal Immunity in gram negative bacterial pneumonia
Journal of Immunology, 2012Co-Authors: Melissa A Kovach, Xianying Zeng, Megan N Ballinger, Michael W. Newstead, Urvashi Bhan, Bethany B Moore, Richard L Gallo, Theodore J. StandifordAbstract:Cathelicidins are a family of endogenous antimicrobial peptides that exert diverse immune functions, including both direct bacterial killing and immunomodulatory effects. In this study, we examined the contribution of the murine cathelicidin, cathelicidin-related antimicrobial peptide (CRAMP), to innate Mucosal Immunity in a mouse model of Gram-negative pneumonia. CRAMP expression is induced in the lung in response to infection with Klebsiella pneumoniae. Mice deficient in the gene encoding CRAMP (Cnlp(-/-)) demonstrate impaired lung bacterial clearance, increased bacterial dissemination, and reduced survival in response to intratracheal K. pneumoniae administration. Neutrophil influx into the alveolar space during K. pneumoniae infection was delayed early but increased by 48 h in CRAMP-deficient mice, which was associated with enhanced expression of inflammatory cytokines and increased lung injury. Bone marrow chimera experiments indicated that CRAMP derived from bone marrow cells rather than structural cells was responsible for antimicrobial effects in the lung. Additionally, CRAMP exerted bactericidal activity against K. pneumoniae in vitro. Similar defects in lung bacterial clearance and delayed early neutrophil influx were observed in CRAMP-deficient mice infected with Pseudomonas aeruginosa, although this did not result in increased bacterial dissemination, increased lung injury, or changes in lethality. Taken together, our findings demonstrate that CRAMP is an important contributor to effective host Mucosal Immunity in the lung in response to Gram-negative bacterial pneumonia.
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flagellin stimulates protective lung Mucosal Immunity role of cathelicidin related antimicrobial peptide
Journal of Immunology, 2010Co-Authors: Matthew D Cornicelli, Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Richard L Gallo, Ashok Kumar, Nan Gao, Sang Gi Yoon, Theodore J. StandifordAbstract:TLRs are required for generation of protective lung Mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial Mucosal Immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung Mucosal innate Immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
Melissa A Kovach - One of the best experts on this subject based on the ideXlab platform.
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il 36γ is a crucial proximal component of protective type 1 mediated lung Mucosal Immunity in gram positive and negative bacterial pneumonia
Mucosal Immunology, 2017Co-Authors: Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Benjamin H Singer, G Martinezcolon, Peter Mancuso, Thomas A Moore, Steven L Kunkel, Marc Petersgolden, Bethany B MooreAbstract:Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in Mucosal Immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung bacterial clearance and increased bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted Immunity in IL-36γ-/- mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate Mucosal Immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.
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redundant and cooperative interactions between tlr5 and nlrc4 in protective lung Mucosal Immunity against pseudomonas aeruginosa
Journal of Innate Immunity, 2014Co-Authors: Fushin X Yu, Melissa A Kovach, Xianying Zeng, Leslie B Tolle, Megan N Ballinger, Michael W. Newstead, Gabriel Nunez, Theodore J. StandifordAbstract:Flagellin is the major structural component of flagella expressed by Pseudomonas aeruginosa (PA) and other bacteria. This protein has been shown to activate the Toll-like receptor TLR5 and the Nod-like receptor Nlrc4/Ipaf, culminating in the expression of innate cytokines and antimicrobial molecules. In this study, we tested the hypothesis that TLR5 and Nlrc4 in combination are required for maximal protective lung innate Mucosal Immunity against PA. To test this hypothesis, we compared innate immune responses in wild-type (WT) C57B6 mice challenged with PA intratracheally to those observed in mice genetically deficient in TLR5 (TLR5-/-) or Nlrc4 (Nlrc4-/-) alone or in combination (TLR5/Nlrc4-/-). As compared to WT, TLR5-/- and Nlrc4-/- mice, we observed a significant increase in mortality in TLR5/Nlrc4-/- mice, which was associated with a >5,000-fold increase in lung PA colony-forming units and systemic bacterial dissemination. The increased mortality observed in double-deficient mice was not attributable to differences in lung leukocyte influx or lung injury responses. Levels of biologically active IL-1β and IL-18 were reduced in the bronchoalveolar lavage fluid from PA-infected Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, indicating the requirement for Nlrc4-dependent caspase-1 activation. Similarly, decreased production of biologically active IL-1β and activation of caspase-1 was observed in PA-stimulated pulmonary macrophages isolated from Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, whereas the expression of iNOS and the production of NO were significantly reduced in cells from double-mutant but not single-mutant mice. Collectively, our findings indicate that TLR5 and Nlrc4 have both unique and redundant roles in lung antibacterial Mucosal Immunity, and the absence of both pathogen recognition receptors results in an increase in susceptibility to invasive lung infection.
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cathelicidin related antimicrobial peptide is required for effective lung Mucosal Immunity in gram negative bacterial pneumonia
Journal of Immunology, 2012Co-Authors: Melissa A Kovach, Xianying Zeng, Megan N Ballinger, Michael W. Newstead, Urvashi Bhan, Bethany B Moore, Richard L Gallo, Theodore J. StandifordAbstract:Cathelicidins are a family of endogenous antimicrobial peptides that exert diverse immune functions, including both direct bacterial killing and immunomodulatory effects. In this study, we examined the contribution of the murine cathelicidin, cathelicidin-related antimicrobial peptide (CRAMP), to innate Mucosal Immunity in a mouse model of Gram-negative pneumonia. CRAMP expression is induced in the lung in response to infection with Klebsiella pneumoniae. Mice deficient in the gene encoding CRAMP (Cnlp(-/-)) demonstrate impaired lung bacterial clearance, increased bacterial dissemination, and reduced survival in response to intratracheal K. pneumoniae administration. Neutrophil influx into the alveolar space during K. pneumoniae infection was delayed early but increased by 48 h in CRAMP-deficient mice, which was associated with enhanced expression of inflammatory cytokines and increased lung injury. Bone marrow chimera experiments indicated that CRAMP derived from bone marrow cells rather than structural cells was responsible for antimicrobial effects in the lung. Additionally, CRAMP exerted bactericidal activity against K. pneumoniae in vitro. Similar defects in lung bacterial clearance and delayed early neutrophil influx were observed in CRAMP-deficient mice infected with Pseudomonas aeruginosa, although this did not result in increased bacterial dissemination, increased lung injury, or changes in lethality. Taken together, our findings demonstrate that CRAMP is an important contributor to effective host Mucosal Immunity in the lung in response to Gram-negative bacterial pneumonia.
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flagellin stimulates protective lung Mucosal Immunity role of cathelicidin related antimicrobial peptide
Journal of Immunology, 2010Co-Authors: Matthew D Cornicelli, Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Richard L Gallo, Ashok Kumar, Nan Gao, Sang Gi Yoon, Theodore J. StandifordAbstract:TLRs are required for generation of protective lung Mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial Mucosal Immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung Mucosal innate Immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
Xianying Zeng - One of the best experts on this subject based on the ideXlab platform.
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il 36γ is a crucial proximal component of protective type 1 mediated lung Mucosal Immunity in gram positive and negative bacterial pneumonia
Mucosal Immunology, 2017Co-Authors: Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Benjamin H Singer, G Martinezcolon, Peter Mancuso, Thomas A Moore, Steven L Kunkel, Marc Petersgolden, Bethany B MooreAbstract:Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in Mucosal Immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung bacterial clearance and increased bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted Immunity in IL-36γ-/- mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate Mucosal Immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.
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redundant and cooperative interactions between tlr5 and nlrc4 in protective lung Mucosal Immunity against pseudomonas aeruginosa
Journal of Innate Immunity, 2014Co-Authors: Fushin X Yu, Melissa A Kovach, Xianying Zeng, Leslie B Tolle, Megan N Ballinger, Michael W. Newstead, Gabriel Nunez, Theodore J. StandifordAbstract:Flagellin is the major structural component of flagella expressed by Pseudomonas aeruginosa (PA) and other bacteria. This protein has been shown to activate the Toll-like receptor TLR5 and the Nod-like receptor Nlrc4/Ipaf, culminating in the expression of innate cytokines and antimicrobial molecules. In this study, we tested the hypothesis that TLR5 and Nlrc4 in combination are required for maximal protective lung innate Mucosal Immunity against PA. To test this hypothesis, we compared innate immune responses in wild-type (WT) C57B6 mice challenged with PA intratracheally to those observed in mice genetically deficient in TLR5 (TLR5-/-) or Nlrc4 (Nlrc4-/-) alone or in combination (TLR5/Nlrc4-/-). As compared to WT, TLR5-/- and Nlrc4-/- mice, we observed a significant increase in mortality in TLR5/Nlrc4-/- mice, which was associated with a >5,000-fold increase in lung PA colony-forming units and systemic bacterial dissemination. The increased mortality observed in double-deficient mice was not attributable to differences in lung leukocyte influx or lung injury responses. Levels of biologically active IL-1β and IL-18 were reduced in the bronchoalveolar lavage fluid from PA-infected Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, indicating the requirement for Nlrc4-dependent caspase-1 activation. Similarly, decreased production of biologically active IL-1β and activation of caspase-1 was observed in PA-stimulated pulmonary macrophages isolated from Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, whereas the expression of iNOS and the production of NO were significantly reduced in cells from double-mutant but not single-mutant mice. Collectively, our findings indicate that TLR5 and Nlrc4 have both unique and redundant roles in lung antibacterial Mucosal Immunity, and the absence of both pathogen recognition receptors results in an increase in susceptibility to invasive lung infection.
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cathelicidin related antimicrobial peptide is required for effective lung Mucosal Immunity in gram negative bacterial pneumonia
Journal of Immunology, 2012Co-Authors: Melissa A Kovach, Xianying Zeng, Megan N Ballinger, Michael W. Newstead, Urvashi Bhan, Bethany B Moore, Richard L Gallo, Theodore J. StandifordAbstract:Cathelicidins are a family of endogenous antimicrobial peptides that exert diverse immune functions, including both direct bacterial killing and immunomodulatory effects. In this study, we examined the contribution of the murine cathelicidin, cathelicidin-related antimicrobial peptide (CRAMP), to innate Mucosal Immunity in a mouse model of Gram-negative pneumonia. CRAMP expression is induced in the lung in response to infection with Klebsiella pneumoniae. Mice deficient in the gene encoding CRAMP (Cnlp(-/-)) demonstrate impaired lung bacterial clearance, increased bacterial dissemination, and reduced survival in response to intratracheal K. pneumoniae administration. Neutrophil influx into the alveolar space during K. pneumoniae infection was delayed early but increased by 48 h in CRAMP-deficient mice, which was associated with enhanced expression of inflammatory cytokines and increased lung injury. Bone marrow chimera experiments indicated that CRAMP derived from bone marrow cells rather than structural cells was responsible for antimicrobial effects in the lung. Additionally, CRAMP exerted bactericidal activity against K. pneumoniae in vitro. Similar defects in lung bacterial clearance and delayed early neutrophil influx were observed in CRAMP-deficient mice infected with Pseudomonas aeruginosa, although this did not result in increased bacterial dissemination, increased lung injury, or changes in lethality. Taken together, our findings demonstrate that CRAMP is an important contributor to effective host Mucosal Immunity in the lung in response to Gram-negative bacterial pneumonia.
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flagellin stimulates protective lung Mucosal Immunity role of cathelicidin related antimicrobial peptide
Journal of Immunology, 2010Co-Authors: Matthew D Cornicelli, Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Richard L Gallo, Ashok Kumar, Nan Gao, Sang Gi Yoon, Theodore J. StandifordAbstract:TLRs are required for generation of protective lung Mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial Mucosal Immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung Mucosal innate Immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
Michael W. Newstead - One of the best experts on this subject based on the ideXlab platform.
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il 36γ is a crucial proximal component of protective type 1 mediated lung Mucosal Immunity in gram positive and negative bacterial pneumonia
Mucosal Immunology, 2017Co-Authors: Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Benjamin H Singer, G Martinezcolon, Peter Mancuso, Thomas A Moore, Steven L Kunkel, Marc Petersgolden, Bethany B MooreAbstract:Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in Mucosal Immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung bacterial clearance and increased bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted Immunity in IL-36γ-/- mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate Mucosal Immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.
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redundant and cooperative interactions between tlr5 and nlrc4 in protective lung Mucosal Immunity against pseudomonas aeruginosa
Journal of Innate Immunity, 2014Co-Authors: Fushin X Yu, Melissa A Kovach, Xianying Zeng, Leslie B Tolle, Megan N Ballinger, Michael W. Newstead, Gabriel Nunez, Theodore J. StandifordAbstract:Flagellin is the major structural component of flagella expressed by Pseudomonas aeruginosa (PA) and other bacteria. This protein has been shown to activate the Toll-like receptor TLR5 and the Nod-like receptor Nlrc4/Ipaf, culminating in the expression of innate cytokines and antimicrobial molecules. In this study, we tested the hypothesis that TLR5 and Nlrc4 in combination are required for maximal protective lung innate Mucosal Immunity against PA. To test this hypothesis, we compared innate immune responses in wild-type (WT) C57B6 mice challenged with PA intratracheally to those observed in mice genetically deficient in TLR5 (TLR5-/-) or Nlrc4 (Nlrc4-/-) alone or in combination (TLR5/Nlrc4-/-). As compared to WT, TLR5-/- and Nlrc4-/- mice, we observed a significant increase in mortality in TLR5/Nlrc4-/- mice, which was associated with a >5,000-fold increase in lung PA colony-forming units and systemic bacterial dissemination. The increased mortality observed in double-deficient mice was not attributable to differences in lung leukocyte influx or lung injury responses. Levels of biologically active IL-1β and IL-18 were reduced in the bronchoalveolar lavage fluid from PA-infected Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, indicating the requirement for Nlrc4-dependent caspase-1 activation. Similarly, decreased production of biologically active IL-1β and activation of caspase-1 was observed in PA-stimulated pulmonary macrophages isolated from Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, whereas the expression of iNOS and the production of NO were significantly reduced in cells from double-mutant but not single-mutant mice. Collectively, our findings indicate that TLR5 and Nlrc4 have both unique and redundant roles in lung antibacterial Mucosal Immunity, and the absence of both pathogen recognition receptors results in an increase in susceptibility to invasive lung infection.
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cathelicidin related antimicrobial peptide is required for effective lung Mucosal Immunity in gram negative bacterial pneumonia
Journal of Immunology, 2012Co-Authors: Melissa A Kovach, Xianying Zeng, Megan N Ballinger, Michael W. Newstead, Urvashi Bhan, Bethany B Moore, Richard L Gallo, Theodore J. StandifordAbstract:Cathelicidins are a family of endogenous antimicrobial peptides that exert diverse immune functions, including both direct bacterial killing and immunomodulatory effects. In this study, we examined the contribution of the murine cathelicidin, cathelicidin-related antimicrobial peptide (CRAMP), to innate Mucosal Immunity in a mouse model of Gram-negative pneumonia. CRAMP expression is induced in the lung in response to infection with Klebsiella pneumoniae. Mice deficient in the gene encoding CRAMP (Cnlp(-/-)) demonstrate impaired lung bacterial clearance, increased bacterial dissemination, and reduced survival in response to intratracheal K. pneumoniae administration. Neutrophil influx into the alveolar space during K. pneumoniae infection was delayed early but increased by 48 h in CRAMP-deficient mice, which was associated with enhanced expression of inflammatory cytokines and increased lung injury. Bone marrow chimera experiments indicated that CRAMP derived from bone marrow cells rather than structural cells was responsible for antimicrobial effects in the lung. Additionally, CRAMP exerted bactericidal activity against K. pneumoniae in vitro. Similar defects in lung bacterial clearance and delayed early neutrophil influx were observed in CRAMP-deficient mice infected with Pseudomonas aeruginosa, although this did not result in increased bacterial dissemination, increased lung injury, or changes in lethality. Taken together, our findings demonstrate that CRAMP is an important contributor to effective host Mucosal Immunity in the lung in response to Gram-negative bacterial pneumonia.
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flagellin stimulates protective lung Mucosal Immunity role of cathelicidin related antimicrobial peptide
Journal of Immunology, 2010Co-Authors: Matthew D Cornicelli, Melissa A Kovach, Xianying Zeng, Michael W. Newstead, Richard L Gallo, Ashok Kumar, Nan Gao, Sang Gi Yoon, Theodore J. StandifordAbstract:TLRs are required for generation of protective lung Mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial Mucosal Immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung Mucosal innate Immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
Gregory M. Lamonte - One of the best experts on this subject based on the ideXlab platform.
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Dual RNA-seq identifies human Mucosal Immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection
Nature Communications, 2019Co-Authors: Gregory M. Lamonte, Justine Swann, Pamela Orjuela-sanchez, Jaeson Calla, Lawrence T. Wang, Shangzhong Li, Annie N. Cowell, Alyaa M. Abdel-haleem Mohamed, Zaira Hellen Villa Galarce, Marta MorenoAbstract:Host-parasite interactions during the exoerythrocytic stage of Plasmodium infection remains poorly understood. Using dual RNA-Seq, the authors show that human Mucosal Immunity protein mucin-13 is upregulated during Plasmodium hepatic-stage infection and marks infected cells independent of tested Plasmodium species. The exoerythrocytic stage of Plasmodium infection is a critical window for prophylactic intervention. Using genome-wide dual RNA sequencing of flow-sorted infected and uninfected hepatoma cells we show that the human Mucosal Immunity gene, mucin-13 (MUC13), is strongly upregulated during Plasmodium exoerythrocytic hepatic-stage infection. We confirm MUC13 transcript increases in hepatoma cell lines and primary hepatocytes. In immunofluorescence assays, host MUC13 protein expression distinguishes infected cells from adjacent uninfected cells and shows similar colocalization with parasite biomarkers such as UIS4 and HSP70. We further show that localization patterns are species independent, marking both P. berghei and P. vivax infected cells, and that MUC13 can be used to identify compounds that inhibit parasite replication in hepatocytes. This data provides insights into host-parasite interactions in Plasmodium infection, and demonstrates that a component of host Mucosal Immunity is reprogrammed during the progression of infection.
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Dual RNA-seq identifies human Mucosal Immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection.
Nature Communications, 2019Co-Authors: Gregory M. Lamonte, Justine Swann, Pamela Orjuela-sanchez, Jaeson Calla, Lawrence T. Wang, Shangzhong Li, Annie N. Cowell, Alyaa Mohamed, Zaira Hellen Villa GalarceAbstract:The exoerythrocytic stage of Plasmodium infection is a critical window for prophylactic intervention. Using genome-wide dual RNA sequencing of flow-sorted infected and uninfected hepatoma cells we show that the human Mucosal Immunity gene, mucin-13 (MUC13), is strongly upregulated during Plasmodium exoerythrocytic hepatic-stage infection. We confirm MUC13 transcript increases in hepatoma cell lines and primary hepatocytes. In immunofluorescence assays, host MUC13 protein expression distinguishes infected cells from adjacent uninfected cells and shows similar colocalization with parasite biomarkers such as UIS4 and HSP70. We further show that localization patterns are species independent, marking both P. berghei and P. vivax infected cells, and that MUC13 can be used to identify compounds that inhibit parasite replication in hepatocytes. This data provides insights into host-parasite interactions in Plasmodium infection, and demonstrates that a component of host Mucosal Immunity is reprogrammed during the progression of infection.
