The pathogen-associated
            <i>iroA</i>
            gene cluster mediates bacterial evasion of lipocalin 2

Fischbach, Michael A.; Lin, Hening; Zhou, Lu; Yu, Yang; Abergel, Rebecca J.; Liu, David R.; Raymond, Kenneth N.; Wanner, Barry L.; Strong, Roland K.; Walsh, Christopher T.; Aderem, Alan; Smith, Kelly D.

doi:10.1073/pnas.0604636103

Cited by 274 publications

(248 citation statements)

References 35 publications

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“…Within phagocytes, however, S. typhimurium has limited access to mammalian iron resources. Therefore, Salmonella has evolved both siderophore-dependent and -independent mechanisms to acquire iron from intracellular host sources; on the one hand, S. typhimurium produces enterochelin and salmochelins via its enzymes entC and iroB, respectively, the latter encoded within the iroA gene cluster [16,17]. On the other hand, non-siderophorebound ferrous iron is taken up by Feo, a pathway that may be most relevant in microenvironments with low oxygen tension [18].…”

Section: Introductionmentioning

confidence: 99%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

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In stimulating effector functions of mononuclear phagocytes, IFN-c is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-c is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-c on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-c caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-c exerting a super-inducing effect. This observed regulatory impact of IFN-c reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-a production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-c concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. IntroductionHost defense against intracellular microbes such as salmonellae or mycobacteria strongly depends on cell-mediated immunity, a major component of which is characterized by interactions between Th1 cells and macrophages [1]. By secreting Th1 cytokines, particularly IFN-c, antigen-specific Th1 cells activate a plethora of microbicidal mechanisms in infected macrophages. Specifically, in mononuclear phagocytes infected with Salmonella enterica serovar typhimurium (S. typhimurium), IFN-c promotes the internalization of bacteria and stimulates their elimination by various mechanisms including reactive oxygen and nitrogen species (ROS and RNS), generated via NADPH phagocyte oxidase and iNOS, respectively [2][3][4][5]. In Salmonella-infected mice, treatment with recombinant IFN-c increases host survival and decreases bacterial numbers in liver and spleen [6]. Conversely, neutralization of murine IFN-c functions with specific antibodies results in reduced host survival and increased bacterial counts [7]. Eur. J. Immunol. 2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virule...

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Section: Introductionmentioning

confidence: 99%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

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“…3A). Lipocalin-2 (lcn2) binds to bacterial enterochelins, thereby sequestering iron and depriving pathogens like Escherichia coli of this essential growth factor (17,18). Furthermore, it has recently been published that, in macrophages stimulated with heatkilled group B streptococci (GBS), the induction of lipocalin-2 was severely impaired in the absence of TLR2 signaling (13).…”

Section: Expression Of Ifn-regulated Genes Is Partially Dependent On mentioning

confidence: 99%

MyD88-dependent changes in the pulmonary transcriptome after infection withChlamydia pneumoniae

Rodríguez

Mages

Dietrich

et al. 2007

Physiological Genomics

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, an intracellular bacterium, causes pneumonia in humans and mice. Toll-like receptors and the key adaptor molecule myeloid differentiation factor-88 (MyD88) play a critical role in inducing immunity against this microorganism and are crucial for survival. To explore the influence of MyD88 on induction of immune responses in vivo on a genome-wide level, wildtype (WT) or MyD88 Ϫ/Ϫ mice were infected with C. pneumoniae on anesthesia, and the pulmonary transcriptome was analyzed 3 days later by microarrays. We found that the infection caused pulmonary cellular infiltration in WT but not MyD88 Ϫ/Ϫ mice. Furthermore, it induced the transcription of 360 genes and repressed 18 genes in WT mice. Of these, 221 genes were not or weakly induced in lungs of MyD88 Ϫ/Ϫ mice. This cluster contains primarily genes encoding for chemokines and cytokines like MIP-1␣, MIP-2, MIP-1␥, MCP-1, TNF, and KC and other immune effector molecules like immunoresponsive gene-1 and TLR2. Arginase was highly induced after C. pneumoniae infection and was MyD88 dependent. Genes induced by interferons were abundant in a cluster of 102 genes that were only partially MyD88 dependent. Also, lcn2 (lipocalin-2) and timp1 were represented within this cluster. Interestingly, a set of 37 genes including sprr1a was induced more strongly in MyD88 Ϫ/Ϫ mice, and most of them are involved in the regulation of cellular replication. In summary, ex vivo analysis of the pulmonary transcriptome on infection with C. pneumoniae demonstrated a major impact of MyD88 on inflammatory responses but not on interferon-type responses and identified MyD88-independent genes involved in cellular replication.

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“…17 Lcn-2 exerts its growthinhibitory effect by binding several ferric siderophore complexes such as siderophore enterobactin (Ent), which is produced by Gram-negative enteric bacteria, including Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae. 18,19 Besides working as a bacteriostatic protein, Lcn-2 has been reported to be involved in the pathogenesis of inflammation and cancer. 20 In light of these reports, it is possible that Lcn-2 may affect inflammatory responses induced by ETBF-derived BFT and subsequently contribute to host defense.…”

mentioning

confidence: 99%

Bacteroides fragilis enterotoxin upregulates lipocalin-2 expression in intestinal epithelial cells

Yoo

Jung

et al. 2013

Laboratory Investigation

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Enterotoxigenic Bacteroides fragilis (ETBF) produces an B20 kDa B. fragilis enterotoxin (BFT), which plays an essential role in mucosal inflammation. Lipocalin (Lcn)-2, a siderophore-binding antimicrobial protein, is critical for control of bacterial infection; however, expression of Lcn-2 in BFT-exposed intestinal epithelial cells has not been elucidated. In the present study, stimulation of human intestinal epithelial cells with BFT resulted in the upregulation of Lcn-2 expression that was a relatively late response of intestinal epithelial cells compared with human b-defensin (hBD)-2 expression. The upregulation of Lcn-2 was dependent on AP-1 but not on NF-kB signaling. Lcn-2 induction via AP-1 was regulated by mitogenactivated protein kinases (MAPKs) including ERK and p38. Lcn-2 was secreted from the apical and basolateral surfaces in BFT-treated cells. These results suggest that a signaling pathway involving MAPKs and AP-1 is required for Lcn-2 induction in intestinal epithelial cells exposed to BFT, after which the secreted Lcn-2 may facilitate antimicrobial activity within ETBF-infected mucosa.

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The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2

Cited by 274 publications

References 35 publications

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

MyD88-dependent changes in the pulmonary transcriptome after infection withChlamydia pneumoniae

Bacteroides fragilis enterotoxin upregulates lipocalin-2 expression in intestinal epithelial cells

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