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  1. Article ; Online: Myeloid deletion of talin-1 reduces mucosal macrophages and protects mice from colonic inflammation

    Yvonne L. Latour / Kara M. McNamara / Margaret M. Allaman / Daniel P. Barry / Thaddeus M. Smith / Mohammad Asim / Kamery J. Williams / Caroline V. Hawkins / Justin Jacobse / Jeremy A. Goettel / Alberto G. Delgado / M. Blanca Piazuelo / M. Kay Washington / Alain P. Gobert / Keith T. Wilson

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors ... ...

    Abstract Abstract The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors that are highly involved in immune cell adhesion to endothelial cells while in the circulation and help facilitate extravasation into tissues. Here we show that specific deletion of the Tln1 gene encoding the protein talin-1, an integrin-activating scaffold protein, from cells of the myeloid lineage using the Lyz2-cre driver mouse reduces epithelial damage, attenuates colitis, downregulates the expression of macrophage markers, decreases the number of differentiated colonic mucosal macrophages, and diminishes the presence of CD68-positive cells in the colonic mucosa of mice infected with the enteric pathogen Citrobacter rodentium. Bone marrow-derived macrophages lacking expression of Tln1 did not exhibit a cell-autonomous phenotype; there was no impaired proinflammatory gene expression, nitric oxide production, phagocytic ability, or surface expression of CD11b, CD86, or major histocompatibility complex II in response to C. rodentium. Thus, we demonstrate that talin-1 plays a role in the manifestation of infectious colitis by increasing mucosal macrophages, with an effect that is independent of macrophage activation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570 ; 616
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Hypusination Orchestrates the Antimicrobial Response of Macrophages

    Alain P. Gobert / Jordan L. Finley / Yvonne L. Latour / Mohammad Asim / Thaddeus M. Smith / Thomas G. Verriere / Daniel P. Barry / Margaret M. Allaman / Alberto G. Delagado / Kristie L. Rose / M. Wade Calcutt / Kevin L. Schey / Johanna C. Sierra / M. Blanca Piazuelo / Raghavendra G. Mirmira / Keith T. Wilson

    Cell Reports, Vol 33, Iss 11, Pp 108510- (2020)

    2020  

    Abstract: Summary: Innate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor ...

    Abstract Summary: Innate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor 5A (EIF5A) to form the amino acid hypusine. Hypusinated EIF5A (EIF5AHyp) transports specific mRNAs to ribosomes for translation. We show that DHPS is induced in macrophages by two gastrointestinal pathogens, Helicobacter pylori and Citrobacter rodentium, resulting in enhanced hypusination of EIF5A. EIF5AHyp was also increased in gastric macrophages from patients with H. pylori gastritis. Furthermore, we identify the bacteria-induced immune effectors regulated by hypusination. This set of proteins includes essential constituents of antimicrobial response and autophagy. Mice with myeloid cell-specific deletion of Dhps exhibit reduced EIF5AHyp in macrophages and increased bacterial burden and inflammation. Thus, regulation of translation through hypusination is a critical hallmark of the defense of eukaryotic hosts against pathogenic bacteria.
    Keywords macrophages ; bacterial infection ; innate immunity ; hypusine ; polyamines ; Helicobacter pylori ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: NsrR, GadE, and GadX interplay in repressing expression of the Escherichia coli O157:H7 LEE pathogenicity island in response to nitric oxide.

    Priscilla Branchu / Stéphanie Matrat / Marjolaine Vareille / Annie Garrivier / Alexandra Durand / Sébastien Crépin / Josée Harel / Grégory Jubelin / Alain P Gobert

    PLoS Pathogens, Vol 10, Iss 1, p e

    2014  Volume 1003874

    Abstract: Expression of genes of the locus of enterocyte effacement (LEE) is essential for adherence of enterohemorrhagic Escherichia coli (EHEC) to intestinal epithelial cells. Gut factors that may modulate LEE gene expression may therefore influence the outcome ... ...

    Abstract Expression of genes of the locus of enterocyte effacement (LEE) is essential for adherence of enterohemorrhagic Escherichia coli (EHEC) to intestinal epithelial cells. Gut factors that may modulate LEE gene expression may therefore influence the outcome of the infection. Because nitric oxide (NO) is a critical effector of the intestinal immune response that may induce transcriptional regulation in enterobacteria, we investigated its influence on LEE expression in EHEC O157:H7. We demonstrate that NO inhibits the expression of genes belonging to LEE1, LEE4, and LEE5 operons, and that the NO sensor nitrite-sensitive repressor (NsrR) is a positive regulator of these operons by interacting directly with the RNA polymerase complex. In the presence of NO, NsrR detaches from the LEE1/4/5 promoter regions and does not activate transcription. In parallel, two regulators of the acid resistance pathway, GadE and GadX, are induced by NO through an indirect NsrR-dependent mechanism. In this context, we show that the NO-dependent LEE1 down-regulation is due to absence of NsrR-mediated activation and to the repressor effect of GadX. Moreover, the inhibition of expression of LEE4 and LEE5 by NO is due to loss of NsrR-mediated activation, to LEE1 down-regulation and to GadE up-regulation. Lastly, we establish that chemical or cellular sources of NO inhibit the adherence of EHEC to human intestinal epithelial cells. These results highlight the critical effect of NsrR in the regulation of the LEE pathogenicity island and the potential role of NO in the limitation of colonization by EHEC.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The L-Arginine Transporter Solute Carrier Family 7 Member 2 Mediates the Immunopathogenesis of Attaching and Effacing Bacteria.

    Kshipra Singh / Nicole T Al-Greene / Thomas G Verriere / Lori A Coburn / Mohammad Asim / Daniel P Barry / Margaret M Allaman / Dana M Hardbower / Alberto G Delgado / M Blanca Piazuelo / Bruce A Vallance / Alain P Gobert / Keith T Wilson

    PLoS Pathogens, Vol 12, Iss 10, p e

    2016  Volume 1005984

    Abstract: Solute carrier family 7 member 2 (SLC7A2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in immune responses to pathogens. We assessed the role of SLC7A2 in murine infection with Citrobacter ... ...

    Abstract Solute carrier family 7 member 2 (SLC7A2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in immune responses to pathogens. We assessed the role of SLC7A2 in murine infection with Citrobacter rodentium, an attaching and effacing enteric pathogen that causes colitis. Induction of SLC7A2 was upregulated in colitis tissues, and localized predominantly to colonic epithelial cells. Compared to wild-type mice, Slc7a2-/-mice infected with C. rodentium had improved survival and decreased weight loss, colon weight, and histologic injury; this was associated with decreased colonic macrophages, dendritic cells, granulocytes, and Th1 and Th17 cells. In infected Slc7a2-/-mice, there were decreased levels of the proinflammatory cytokines G-CSF, TNF-α, IL-1α, IL-1β, and the chemokines CXCL1, CCL2, CCL3, CCL4, CXCL2, and CCL5. In bone marrow chimeras, the recipient genotype drove the colitis phenotype, indicative of the importance of epithelial, rather than myeloid SLC7A2. Mice lacking Slc7a2 exhibited reduced adherence of C. rodentium to the colonic epithelium and decreased expression of Talin-1, a focal adhesion protein involved in the attachment of the bacterium. The importance of SLC7A2 and Talin-1 in the intimate attachment of C. rodentium and induction of inflammatory response was confirmed in vitro, using conditionally-immortalized young adult mouse colon (YAMC) cells with shRNA knockdown of Slc7a2 or Tln1. Inhibition of L-Arg uptake with the competitive inhibitor, L-lysine (L-Lys), also prevented attachment of C. rodentium and chemokine expression. L-Lys and siRNA knockdown confirmed the role of L-Arg and SLC7A2 in human Caco-2 cells co-cultured with enteropathogenic Escherichia coli. Overexpression of SLC7A2 in human embryonic kidney cells increased bacterial adherence and chemokine expression. Taken together, our data indicate that C. rodentium enhances its own pathogenicity by inducing the expression of SLC7A2 to favor its attachment to the epithelium and ...
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2016-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  5. Article ; Online: Cationic amino acid transporter 2 enhances innate immunity during Helicobacter pylori infection.

    Daniel P Barry / Mohammad Asim / Brooks P Scull / M Blanca Piazuelo / Thibaut de Sablet / Nuruddeen D Lewis / Lori A Coburn / Kshipra Singh / Lesley G Ellies / Alain P Gobert / Rupesh Chaturvedi / Keith T Wilson

    PLoS ONE, Vol 6, Iss 12, p e

    2011  Volume 29046

    Abstract: Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of ... ...

    Abstract Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2) is essential for transport of L-arginine (L-Arg) into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO) produced from inducible NO synthase (iNOS), or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2(-/-) mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2(-/-) mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2(-/-) mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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